HETEROCYCLIC COMPOUND AND p27Kip1 DEGRADATION INHIBITOR

ABSTRACT

A novel heterocyclic compound or a salt thereof useful for selectively inhibiting the degradation of p27 Kip1  is provided. The compound or the salt thereof is represented by the following formula (1): 
     
       
         
         
             
             
         
       
         
         
           
             wherein A represents an alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group, the group A may have a substituent; the ring B represents a 5- to 8-membered monocyclic heterocyclic ring or a condensed ring containing the monocyclic heterocyclic ring, the ring B may have a substituent; the ring C represents an aromatic ring, the ring C may have a substituent; L represents a linker comprising a main chain having 3 to 5 atoms selected from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least one atom in the main chain is a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, the linker L may have a substituent; and n is 0 or 1.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound thatspecifically binds to the component protein Skp2 of ubiquitin ligase(SCF^(Skp2)) and, for example, inhibits the dissociation of p27^(Kip1)from SCF^(Skp2) complex, and that is useful for subsequently inhibitingthe progression of the ubiquitination of p27^(Kip1) and inhibiting thedegradation of p27^(Kip1) by a proteasome; a p27^(Kip1) ubiquitinationinhibitor (or a p27^(Kip1) degradation inhibitor) containing thecompound; and an agent for preventing and/or treating a cellproliferative disease (for example, an anticancer agent).

BACKGROUND ART

p27^(Kip1) is one of cyclin-dependent kinase inhibitors (CDK Inhibitors)that are a factor negatively regulating cell cycle progression. Clinicalstudies have revealed that the accelerated degradation of p27^(Kip1)decreases the expression amount of p27^(Kip1) in highly malignant cancercells. Moreover, clinical studies suggest that the decrease in theexpression amount of p27^(Kip1) closely relates to the progression,recurrence and metastasis of cancer and the decrease of survival ratioof patients with cancer.

p27^(Kip1) is mainly decomposed by ubiquitin-proteasome system todecrease in the amount of expression. More specifically, if threonine187 of p27^(Kip1) is phosphorylated, p27^(Kip1) is isolated from acyclin-CDK complex to specifically bind to Fbox protein (Skp2) of aubiquitin ligase comprising a SCF (Skp1/Cullin1/Fbox) complex. Whereas,a ubiquitin conjugating enzyme (E2) binds to the ubiquitin ligasecomplex through Rbx1 in the complex, and p27^(Kip1) binding to Skp2 isubiquitinated through the enzyme. By the repetition of theubiquitination reaction, the polyubiquitinated p27^(Kip1) is recognizedby a proteasome to be decomposed.

Thus the degradation mechanism of p27^(Kip1) has been explainedmolecular-biologically, but an effective p27^(Kip1) degradationinhibitor is still not known.

Incidentally, WO2005/012269 (Patent Document 1) discloses a compoundrepresented by following formula as a physiologically active inhibitorof LPA acting as an intercellular messenger.

This document also discloses that the compound is useful as a treatingor preventing agent for a cell proliferative disease, which is one ofdiseases in which a LPA receptor participates. The document, however, issilent on the relationship between the compound and an intracellularprotein.

RELATED ART DOCUMENTS Patent Documents

Patent Document 1: WO2005/012269 (Claims, Examples)

SUMMARY OF THE INVENTION Problems to be Solved by the Invention

It is therefore an object of the present invention to provide a novelheterocyclic compound or a salt thereof, a degradation inhibitor ofp27^(Kip1), a ubiquitination inhibitor of p27^(Kip1), a preventingand/or treating agent for a cell proliferative disease, and apharmaceutical composition.

Another object of the present invention is to provide a novelheterocyclic compound or a salt thereof effective in selectivelyinhibiting the degradation of p27^(Kip1), a degradation inhibitor ofp27^(Kip1), a ubiquitination inhibitor of p27^(Kip1), a preventingand/or treating agent for a cell proliferative disease, and apharmaceutical composition.

It is still another object of the present invention to provide a novelheterocyclic compound or a salt thereof effective in selectivelyinhibiting the ubiquitination of p27^(Kip1), a degradation inhibitor ofp27^(Kip1), a ubiquitination inhibitor of p27^(Kip1), a preventingand/or treating agent for a cell proliferative disease, and apharmaceutical composition.

Means to Solve the Problems

As a compound acting on the ubiquitin-proteasome system, a proteasomeinhibitor VELCADE (registered trademark) (manufactured by Millennium,generic name “Bortezomib”) non-selectively inhibits substrate proteinsbecause a proteasome has a function to decompose various ubiquitinatedsubstrate proteins. Moreover, MLN4924, which has been reported as aninhibitor of NAE (NEDD8-activating enzyme), acts on all of Cullin-RINGligases (CRLs) containing Cullin protein as a constituent element,thereby inhibiting the degradation of all substrate proteins to beubiquitinated.

Thus, the inventors of the present invention made intensive studies toachieve the above objects based on the knowledge and finally found thata heterocyclic compound or a salt thereof having a plurality of ringslinked to each other through a specific linker (1) specifically binds tothe component protein Skp2 of the ubiquitin ligase (SCF^(Skp2)) and, forexample, inhibits the dissociation p27^(Kip1) from SCF^(Skp2) complex,as a result can inhibit the ubiquitination of p27^(Kip1) and thedegradation of p27^(Kip1) by the proteasome followed by theubiquitination, (2) can selectively inhibit the degradation ofp27^(Kip1) at a high activity, recover the expression amount ofβ27^(Kip1), and thus avoid increase in the non-selective expression ofproteins other than p27^(Kip1), and (3) can induce cell death(apoptosis) of cells having a decreased expression amount of p27^(Kip1)(such as cancer cells). The present invention was accomplished based onthe above findings.

That is, the heterocyclic compound or the salt thereof of the presentinvention is represented by the following formula (1) or a salt thereof.

In the formula, A represents an alkyl group, a cycloalkyl group, an arylgroup or a heterocyclic group, the group A may have a substituent; thering B represents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the monocyclic heterocyclic ring, the ring Bmay have a substituent; the ring C represents an aromatic ring, the ringC may have a substituent; L represents a linker comprising a main chainhaving 3 to 5 atoms selected from the group consisting of a carbon atom,a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least oneatom in the main chain is a hetero atom selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom, thelinker L may have a substituent; and n is 0 or 1.

With the proviso that (i) when n is 0, the ring B is a condensed ringcontaining a 5- to 8-membered monocyclic heterocyclic ring,

(ii) when the ring C is a monocyclic arene ring, the ring C has asubstituent,(iii) when the linker L is a linker represented by the following formula(1-a1):

the group A is a group other than 2-methylaminopyrimidin-4-yl group andthe ring C is a ring other than 9-fluorenyl group,

(iv) when linker L is a linker represented by the following formula(1-a2):

wherein X¹ represents methyl group and the ring C is a benzene ringhaving a halogen atom as a substituent,

the ring B is a ring other than 3,4-isoxazole-diyl group.

In the formula (1), the linker L may contain a urethane bond or linkage[—NH—C(O)—O— or —O—C(O)—NH—]. For example, the linker L may be a linkerrepresented by each one of the following formulae (1-a1) to (1-a6):

wherein X¹ represents an alkyl group.

In the formula (1), the group A may be an aryl or heterocyclic grouphaving at least one substituent selected from the group consisting of ahalogen atom, an alkyl group, a hydroxyl group, an alkoxy group, amercapto group and an alkylthio group, for example, may be a phenylgroup having substituent(s) on 2-position and/or 4-position.

In the formula (1), the ring B may be an aromatic heterocyclic ringcontaining at least one hetero atom selected from the group consistingof a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S) as aconstituent atom thereof. For example, the ring B may be an aromaticheterocyclic ring selected from the group consisting of a pyrrole ring,a furan ring, a thiophene ring, an imidazole ring, a pyrazole ring, athiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring,a thiadiazole ring, a pyridine ring, a pyrimidine ring and a quinolinering (in particular, a 5- or 6-membered monocyclic heterocyclic ringsuch as a thiazole ring, an isothiazole ring or a pyrazole ring).

In the formula (1), the aromatic ring represented by the ring C is notparticularly limited to a specific one. For example, the aromatic ringis practically a monocyclic (non-condensed) arene ring having asubstituent, a condensed arene ring which may have a substituent, or amonocyclic (non-condensed) or condensed heterocyclic ring which may havea substituent. The ring C may for example be each one of the followingformulae (4-a) to (4-c):

wherein Z¹ represents a halogen atom, an alkyl group, a hydroxyl group,an alkoxy group, a mercapto group, an alkylthio group, anN-alkyl-substituted amino group (such as an N,N-dialkylamino group) oran N-acyl-substituted amino group (such as an N,N-diacylamino group); Z²represents an alkyl group or an acyl group; Z³ represents an alkyl groupor an acyl group; the ring C¹ represents a C₆₋₁₀arene ring; the ring C²represents a 5- to 8-membered heterocyclic ring comprising G¹ and G²,the ring containing at least one hetero atom selected from the groupconsisting of a nitrogen atom (N), an oxygen atom (O) and a sulfur atom(S) as a constituent atom thereof; the ring C³ represents a 5- to8-membered heterocyclic ring comprising G⁴ of the ring adjacent thereto,the ring C³ containing at least one hetero atom selected from the groupconsisting of a nitrogen atom (N), an oxygen atom (O) and a sulfur atom(S) as a constituent atom thereof; G¹ to G³ each represent a nitrogenatom (N), an oxygen atom (O), a sulfur atom (S), NH, CH or CH₂ dependingon the aromaticity or nonaromaticity of the ring C² or that of the5-membered ring adjacent to the ring C³; G⁴ represents a nitrogen atom(N), a carbon atom (C) or CH depending on the aromaticity ornonaromaticity of the 5-membered ring adjacent to the ring C³; p is aninteger of 1 to 5, and q is an integer of 0 to 6.

In the 5-membered ring which is adjacent to the ring C³ and contains G³and G⁴, the broken line indicates that the 5-membered ring may be anaromatic ring or a nonaromatic (aliphatic) ring.

As concrete examples of the compound or the salt thereof, there may bementioned compounds or salts thereof, each represented by any one of thefollowing formulae (6-a) to (6-c):

wherein R¹ and R² are the same or different and each represent a halogenatom, an alkyl group, a hydroxyl group, an alkoxy group, a mercaptogroup or an alkylthio group; the ring B represents a thiazole ring, anisothiazole ring or a pyrazole ring, the ring B may have at least onesubstituent selected from the group consisting of an alkyl group, ahaloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group andan acyl group; L represents a linker selected from the group consistingof the formulae (1-a1) to (1-a6); Z^(a) represents a hydroxyl group, analkoxy group, a mercapto group, an alkylthio group, anN-alkyl-substituted amino group (such as an N,N-dialkylamino group) oran N-acyl-substituted amino group (such as an N,N-diacylamino group);Z^(b) represents a hydrogen atom, an alkyl group, a hydroxyl group or analkoxy group; G¹ represents a nitrogen atom (N), CH or CH₂ depending onthe aromaticity or nonaromaticity of the ring C²; G² represents anitrogen atom (N), an oxygen atom (O) or NH; the ring C², the ring C³,Z², Z³ and q have the same meanings as defined above.

The pharmaceutical composition of the present invention comprises thecompound or a pharmaceutically (or physiologically) acceptable saltthereof and a carrier.

The heterocyclic compound or the salt thereof represented by thefollowing formula (1):

wherein A represents an alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic group, the group A may have a substituent; the ring Brepresents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the monocyclic heterocyclic ring, the ring Bmay have a substituent; the ring C represents an aromatic ring, the ringC may have a substituent; L represents a linker comprising a main chainhaving 3 to 5 atoms selected from the group consisting of a carbon atom,a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least oneatom in the main chain is a hetero atom selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom, thelinker L may have a substituent; and n is 0 or 1;

with the proviso that (i) when n is 0, the ring B is a condensed ringcontaining a 5- to 8-membered monocyclic heterocyclic ring,

(ii) when the ring C is a monocyclic arene ring, the ring C has asubstituent;

specifically binds to the component protein Skp2 of ubiquitin ligase(SCF^(Skp2)) and, for example, inhibits the dissociation of p27^(Kip1)from SCF^(Skp2) complex, and as a result can effectively inhibit theubiquitination of p27^(Kip1) and the degradation of p27^(Kip1) by theproteasome followed by the ubiquitination. Thus, the present inventionincludes a p27^(Kip1) ubiquitination inhibitor or degradation inhibitorcontaining the compound or a pharmaceutically (or physiologically)acceptable salt thereof as an effective ingredient.

Further, the heterocyclic compound or the salt thereof represented bythe following formula (1):

wherein A represents an alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic group, the group A may have a substituent; the ring Brepresents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the monocyclic heterocyclic ring, the ring Bmay have a substituent; the ring C represents an aromatic ring, the ringC may have a substituent; L represents a linker comprising a main chainhaving 3 to 5 atoms selected from the group consisting of a carbon atom,a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least oneatom in the main chain is a hetero atom selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom, thelinker L may have a substituent; n is 0 or 1;

with the proviso that (i) when n is 0, the ring B is a condensed ringcontaining a 5- to 8-membered monocyclic heterocyclic ring,

(ii) when the ring C is a monocyclic arene ring, the ring C has asubstituent,(iii) when the linker L is a linker represented by the following formula(1-a2):

wherein X¹ represents methyl group and the ring C is a benzene ringhaving a halogen atom as a substituent,

the ring B is a ring other than 3,4-isoxazole-diyl group; can inhibitthe decomposition of the p27^(Kip1) effectively and recover theexpression amount of the p27^(Kip1). Thus, the compound or the saltthereof is effective in preventing and/or treating a cell proliferativedisease (for example, cancer, rheumatism, diabetes, adiposis,endometriosis, prostatomegaly, and inflammation). The present inventiontherefore includes an agent for preventing and/or treating a cellproliferative disease, containing the compound or the pharmaceutically(or physiologically) acceptable salt thereof as an effective ingredient.

Effects of the Invention

The compound or the salt thereof of the present invention specificallybinds to the component protein Skp2 of the ubiquitin ligase (SCF^(Skp2))and, for example, inhibits the dissociation of p27^(Kip1) fromSCF^(Skp2) complex, as a result can inhibit the ubiquitination ofp27^(Kip1) and the degradation of p27^(Kip1) by the proteasome followedby the ubiquitination. Moreover, since, differently from proteasomeinhibitor or the like, the compound or the salt thereof can selectivelyinhibit the degradation of p27^(Kip1), the degradation or increasedexpression of proteins other than p27^(Kip1) can be avoided. Further,since the action of the compound or the salt thereof of the presentinvention on cells having a decreased expression of p27^(Kip1) (such ascancer cells) allows the expression amount of p27^(Kip1) to be recoveredto induce the cell death (apoptosis). The compound or the salt thereofis useful for preventing and/or treating a cell proliferative disease(for example, cancer, rheumatism, diabetes, adiposis, endometriosis,prostatomegaly, and inflammation).

There is a report that the component protein Skp2 of the ubiquitinligase (SCF^(Skp2)) is overexpressed in highly malignant cancer cells inwhich the degradation of p27^(Kip1) is accelerated. For such highlymalignant cancer cells, the compound or the salt thereof of the presentinvention binds to Skp2 due to a high activity thereof and canselectively inhibit the ubiquitination of p27^(Kip1), effectively induceapoptosis accompanied by the expression amount of p27^(Kip1) and show ahigh anticancer action.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows results of the compound of Example 9-1 in Test Example 3.

FIG. 2 shows results of the compound of Example 9-25 in Test Example 3.

FIG. 3 shows results of the compound of Example 9-94 in Test Example 3.

FIG. 4 is a graph showing results of the compound of Example 9-1 in TestExample 4.

FIG. 5 is a graph showing results of the compound of Example 9-25 inTest Example 4.

FIG. 6 is a graph showing results of the compound of Example 9-94 inTest Example 4.

DESCRIPTION OF EMBODIMENTS

In the formula (1), the alkyl group represented by the group A mayinclude, for example, a straight chain or branched chain alkyl group(for example, a C₁₋₁₀alkyl group, preferably a C₁₋₆alkyl group, and morepreferably a C₁₋₄alkyl group) such as methyl, ethyl, propyl, isopropyl,butyl, t-butyl, pentyl, hexyl, 2-ethylhexyl, heptyl or octyl group.

As the cycloalkyl group represented by the group A, there may bementioned a C₃₋₁₀cycloalkyl group (preferably a C₄₋₈cycloalkyl group,and more preferably a C₅₋₆cycloalkyl group) such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl group; acrosslinked cyclic cycloalkyl group (e.g., abi- or tricycloalkyl group)such as adamantly group or norbornyl group.

The aryl group represented by the group A may include, for example, aC₆₋₁₀aryl group such as phenyl or naphthyl group.

The heterocyclic group represented by the group A may include variousheterocyclic groups, each having an aromatic or nonaromatic 5- to8-membered heterocyclic ring, for example, a heterocyclic groupcontaining at least one hetero atom selected from the group consistingof a nitrogen atom, an oxygen atom and a sulfur atom [for example, a 5-or 6-membered heterocyclic group, and a condensed ring group of a 5- or6-membered heterocyclic ring and a carbocyclic (hydrocarbon) ring]. Asthe 5- or 6-membered heterocyclic group, for example, there may bementioned a heterocyclic group containing an oxygen atom as a heteroatom, such as a furyl group (such as 2- or 3-furyl group); aheterocyclic group containing a sulfur atom as a hetero atom, such as athienyl group (such as 2- or 3-thienyl group); a heterocyclic groupcontaining a nitrogen atom as a hetero atom, such as a pyridyl group(such as 2-, 3- or 4-pyridyl group) or a pyrazolyl group (such aspyrazol-2-yl group); and a heterocyclic group containing sulfur atom andnitrogen atom as hetero atoms, such as a thiazolyl group (such asthiazol-5-yl group). The condensed ring group of a 5- or 6-memberedheterocyclic ring and a carbocyclic ring (such as a benzene ring) mayinclude, for example, a condensed ring group of a heterocyclic ringcontaining a sulfur atom as a hetero atom and a carbocyclic ring (suchas a benzene ring) [e.g., a benzothienyl group (or thianaphthenyl group)(such as benzo[b]thiophen-3-yl group (or thianaphthen-3-yl group))]; acondensed ring group of a heterocyclic ring containing a nitrogen atomas a hetero atom and a carbocyclic ring (such as a benzene ring) [e.g.,an isoquinolyl group (such as isoquinolin-1-yl group)]; and a condensedring group of a heterocyclic ring containing an oxygen atom as a heteroatom and a carbocyclic ring (such as a benzene ring) [e.g., a coumarylgroup (such as coumaran-5- or 7-yl group) and an alkylenedioxyphenylgroup (e.g., a C₁₋₄alkylenedioxyphenyl group such as2,3-ethylenedioxyphenyl group)].

The group A may have a substituent. The substituent may include ahalogen atom, an alkyl group, a cycloalkyl group, an aryl group, ahydroxyl group, an alkoxy group, a mercapto group, an alkylthio group,an amino group, an N-substituted amino group, and others. Thesubstituent may further have a substituent (such as a halogen atom) toform a haloalkyl group, a haloalkoxy group, and others.

The halogen atom as the substituent of the group A may include afluorine atom and a chlorine atom.

The alkyl group as the substituent of the group A may include theabove-mentioned C₁₋₆alkyl group (preferably a C₁₋₄alkyl group). As thehaloalkyl group as the substituent of the group A, there may bementioned a straight chain or branched chain haloC₁₋₆alkyl group, forexample, a mono- to per-fluoroC₁₋₆alkyl group (preferably a mono- toper-fluoroC₁₋₄alkyl group) such as a fluoromethyl group (e.g.,trifluoromethyl group), a fluoroethyl group (e.g., 2,2,2-trifluoroethylgroup and perfluoroethyl group), or a fluoropropyl group (e.g.,3,3,3,2,2-pentafluoropropyl group and perfluoropropyl group); andchloroalkyl groups corresponding to these fluoroalkyl groups.

As the substituent of the group A, the cycloalkyl group may include aC₃₋₁₀cycloalkyl group (preferably a C₄₋₈cycloalkyl group, and morepreferably a C₅₋₆cycloalkyl group) such as cyclopentyl or cyclohexylgroup; the aryl group may include a C₆₋₁₀aryl group such as phenyl ornaphthyl group.

The alkoxy group as the substituent of the group A may include astraight chain or branched chain alkoxy group (e.g., a C₁₋₁₀alkoxygroup, preferably a C₁₋₆alkoxy group, and more preferably a C₁₋₄alkoxygroup) such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, ort-butoxy group. The haloalkoxy group as the substituent of the group Amay include a straight chain or branched chain haloC₁₋₆alkoxy group, forexample, a mono- to per-fluoroC₁₋₆alkoxy group (preferably a mono- toper-fluoroC₁₋₄alkoxy group) such as a fluoromethoxy group (e.g.,trifluoromethoxy group), a fluoroethoxy group (e.g.,2,2,2-trifluoroethoxy group and perfluoroethoxy group), or afluoropropoxy group (e.g., 3,3,3,2,2-pentafluoropropoxy group andperfluoropropoxy group); and chloroalkoxy groups corresponding to thesefluoroalkoxy groups.

The alkylthio group as the substituent of the group A may include astraight chain or branched chain alkylthio group (e.g., a C₁₋₁₀alkylthiogroup, preferably a C₁₋₆alkylthio group, and more preferably aC₁₋₄alkylthio group) such as methylthio, ethylthio, propylthio,isopropylthio, butylthio, or t-butylthio group.

The N-substituted amino group as the substituent of the group A mayinclude an N-monosubstituted amino group [for example, an N-alkylaminogroup (e.g., an N—C₁₋₆alkylamino group, and preferably anN—C₁₋₄alkylamino group) such as N-methylamino or N-ethylamino group; andan N-acylamino group (e.g., an N—(C₁₋₆alkyl-carbonyl)amino group, andpreferably an N—(C₁₋₄alkyl-carbonyl)amino group) such as N-acetylaminoor N-propionylamino group]; an N,N-disubstituted amino group [forexample, an N,N-dialkylamino group (e.g., an N,N-diC₁₋₆alkylamino group,and preferably an N,N-diC₁₋₄alkylamino group) such as N,N-dimethylamino,N,N-diethylamino, or N-methyl-N-ethylamino group; and an N,N-diacylaminogroup (e.g., an N,N-di(C₁₋₆alkyl-carbonyl)amino group, and preferably anN,N-di(C₁₋₄alkyl-carbonyl)amino group) such as N,N-diacetylamino group];and others.

The alkyl group having a substituent may include an alkyl group havingat least one substituent selected from the group consisting of a halogenatom and an aryl group, for example, a haloC₁₋₆alkyl group (preferably ahaloC₁₋₄alkyl group) as exemplified above and an arylalkyl group (oraralkyl group) [e.g., a C₆₋₁₀arylC₁₋₆alkyl group (preferably aC₆₋₁₀arylC₁₋₄alkyl group) such as benzyl or phenethyl group].

As the cycloalkyl group having a substituent, there may be mentioned analkylcycloalkyl group [for example, a C₁₋₆alkylC₅₋₆cycloalkyl group(preferably a C₁₋₄alkylC₅₋₆cycloalkyl group) such as 2-methylcyclohexylgroup or 2-ethylcyclohexyl group], and others.

The aryl group having a substituent may include, for example, an arylgroup (e.g., a C₆₋₂₄aryl group, preferably a C₆₋₂₀aryl group, and morepreferably a C₆₋₁₈aryl group) having at least one substituent selectedfrom the group consisting of a halogen atom, an alkyl group, a haloalkylgroup, a hydroxyl group, an alkoxy group, a haloalkoxy group, a mercaptogroup, an alkylthio group and an N-substituted amino group.

Concretely, the monosubstituted aryl group may include an aryl grouphaving one substituent selected from the group consisting of a halogenatom, an alkyl group, a haloalkyl group, a hydroxyl group, an alkoxygroup, a haloalkoxy group, and an N-alkyl-substituted amino group [forexample, a haloaryl group (e.g., a haloC₆₋₁₀aryl group) such as 2-, 3-or 4-chlorophenyl group or 2-, 3- or 4-fluorophenyl group; an alkylarylgroup (e.g., a C₁₋₆alkylC₆₋₁₀aryl group, and preferably aC₁₋₄alkylC₆₋₁₀aryl group) such as 2-, 3- or 4-methylphenyl group or 2-,3- or 4-ethylphenyl group; a mono- to per-haloC₁₋₆alkylC₆₋₁₀aryl group(e.g., a mono- to per-fluoroC₁₋₆alkylC₆₋₁₀aryl group, and preferably amono- to per-fluoroC₁₋₄alkylC₆₋₁₀aryl group) such as 2- or4-trifluoromethylphenyl group or 2- or 4-trichloromethylphenyl group; ahydroxyaryl group (e.g., a hydroxyC₆₋₁₀aryl group) such as 2- or4-hydroxyphenyl group; an alkoxyaryl group (e.g., a C₁₋₆alkoxyC₆₋₁₀arylgroup, and preferably a C₁₋₄alkoxyC₆₋₁₀aryl group) such as 2- or4-methoxyphenyl group, 2- or 4-ethoxyphenyl group, or 2- or4-propoxyphenyl group; a haloC₁₋₆alkoxyC₆₋₁₀aryl group (a mono- toper-fluoroC₁₋₆alkoxyC₆₋₁₀aryl group, and preferably a mono- toper-fluoroC₁₋₄alkoxyC₆₋₁₀aryl group); and an N,N-dialkylaminoaryl group(e.g., an N,N-diC₁₋₆alkylaminoC₆₋₁₀aryl group, and preferably anN,N-diC₁₋₄alkylaminoC₆₋₁₀aryl group) such as 4-(N,N-dimethylamino)phenylgroup].

As the disubstituted aryl group, for example, there may be mentioned anaryl group having two substituents, which may be the same or differentfrom each other, selected from the group consisting of a halogen atom,an alkyl group, a hydroxyl group, an alkoxy group, a mercapto group andan alkylthio group [for example, a dihaloaryl group (e.g., adihaloC₆₋₁₀aryl group) such as 2,3-, 2,4- or 3,4-dichlorophenyl group,2,3-, 2,4- or 3,4-difluorophenyl group, 2-chloro-4-fluorophenyl group or2-fluoro-4-chlorophenyl group; a dialkylaryl group (e.g., adiC₁₋₆alkylC₆₋₁₀aryl group, and preferably a diC₁₋₄alkylC₆₋₁₀aryl group)such as 2,3-, 2,4- or 2,5-dimethylphenyl group; a dihydroxyaryl group(e.g., a dihydroxyC₆₋₁₀aryl group) such as 2,3-, 2,4-, 2,6- or3,4-dihydroxyphenyl group; a dialkoxyaryl group (e.g., adiC₁₋₆alkoxyC₆₋₁₀aryl group, and preferably a diC₁₋₄alkoxyphenyl group)such as 2,3-, 2,4-, 2,6- or 3,4-dimethoxyphenyl group; an alkyl-haloarylgroup (e.g., a C₁₋₆alkyl-haloC₆₋₁₀aryl group, and preferably aC₁₋₄alkyl-haloC₆₋₁₀aryl group) such as 2-methyl-3-(or 4-)chlorophenylgroup or 2-methyl-3-(or 4-)fluorophenyl group; a hydroxy-haloaryl group(e.g., a hydroxy-haloC₆₋₁₀aryl group) such as 2-hydroxy-4-chlorophenylgroup, 2-hydroxy-4-fluorophenyl group, 2-chloro-4-hydroxyphenyl group or2-fluoro-4-hydroxyphenyl group; an alkoxy-haloaryl group (e.g., aC₁₋₆alkoxy-haloC₆₋₁₀aryl group, and preferably aC₁₋₄alkoxy-haloC₆₋₁₀aryl group) such as 2-methoxy-4-chlorophenyl group,2-methoxy-4-fluorophenyl group, 2-chloro-4-methoxyphenyl group or2-fluoro4-methoxyphenyl group; an alkyl-hydroxyaryl group (e.g., aC₁₋₆alkyl-hydroxyC₆₋₁₀aryl group, and preferably aC₁₋₄alkyl-hydroxyC₆₋₁₀aryl group) such as 2-methyl-3-(or4-)hydroxyphenyl group or 2-hydroxy-4-methylphenyl group; and analkyl-alkoxyaryl group (e.g., a C₁₋₆alkyl-C₁₋₆alkoxyC₆₋₁₀aryl group, andpreferably a C₁₋₄alkyl-C₁₋₄alkoxyC₆₋₁₀aryl group) such as 2-methyl-3-(or4-)methoxyphenyl group or 2-methoxy-4-methylphenyl group.

The heterocyclic group having a substituent may include a groupcomprising a heterocyclic ring (e.g., a 5- to 8-membered ring,preferably a 5- to 7-membered heterocyclic group, more preferably a 5-or 6-membered heterocyclic group) that is a heterocyclic ring (e.g., anaromatic heterocyclic ring) containing at least one hetero atom selectedfrom the group consisting of a nitrogen atom, an oxygen atom and asulfur atom and having at least one substituent selected from the groupconsisting of a halogen atom, an alkyl group, a hydroxyl group, analkoxy group, a mercapto group and an alkylthio group. Concretely, theremay be mentioned a heterocyclic group having a halogen atom and/or analkyl group as substituent(s), for example, a heterocyclic group havinga halogen atom as a substituent [for example, a 5- or 6-memberedheterocyclic group containing a nitrogen atom as a hetero atom, e.g., ahalopyridyl group (e.g., a chloropyridyl group such as3-chloropyridin-2-yl group, and a fluoropyridyl group corresponding toeach of the chloropyridyl groups); a 5- or 6-membered heterocyclic groupcontaining an oxygen atom as a hetero atom, e.g., a halofuryl group(e.g., a chlorofuryl group such as 3-chlorofuran-2-yl group, and afluorofuryl group corresponding to each of the chlorofuryl groups); anda 5- or 6-membered heterocyclic group containing a sulfur atom as ahetero atom, e.g., a halothienyl group (e.g., a chlorothienyl group suchas 3- or 5-chlorothiophen-2-yl group or 3,5-dichlorothiophen-2-yl group,and a fluorothienyl group corresponding to each of the chlorothienylgroups)] and a heterocyclic group having an alkyl group as a substituent[for example, a 5- or 6-membered heterocyclic group containing anitrogen atom as a hetero atom, e.g., an alkylpyridyl group (e.g., amono- or di-C₁₋₄alkylpyridyl group such as 3-methylpyridin-2-yl group or4-methylpyridin-3-yl group) and an alkylpyrazolyl group (e.g., a mono-or di-C₁₋₄alkylpyrazolyl group such as (1,4-dimethyl)pyrazol-2-ylgroup); and a 5- or 6-membered heterocyclic group containing a sulfuratom and a nitrogen atom as hetero atoms, e.g., an alkylthiazolyl group(e.g., a mono- or di-C₁₋₄alkylthiazolyl group such as(4-methyl)thiazol-5-yl group or (2,4-dimethyl)thiazol-5-yl group)].

The preferred group A includes an aryl or heterocyclic group having asubstituent (for example, an aryl or heterocyclic group having at leastone substituent selected from the group consisting of a halogen atom, analkyl group, a hydroxyl group, an alkoxy group, a mercapto group and analkylthio group). The number of substituents of the aryl or heterocyclicgroup is, for example, about 1 to 5, preferably about 1 to 4, and morepreferably about 1 to 3 (e.g., 1 or 2), depending on the species of thearyl or heterocyclic group. There is no particular limitation as to theposition of the substituent in the aryl or heterocyclic group. Forexample, for a phenyl group or a 5- or 6-membered heterocyclic group,the substituent may be located at 2-, 3-, or 4-position. If the numberof substituents is not less than 2, the position of the substituentpractically contains at least 2-position and/or 4-position.

The further preferred group A includes a C₆₋₁₀aryl group having asubstituent, for example, a group represented by the following formula(2):

wherein R^(a) to R^(e) are the same or different and each represent ahydrogen atom, a halogen atom, an alkyl group, a haloalkyl group, ahydroxyl group, an alkoxy group, a haloalkoxy group, a mercapto group oran alkylthio group; with the proviso that groups in which all of R^(a)to R^(e) are hydrogen atoms are excluded.

The halogen atom, alkyl group, haloalkyl group, alkoxy group, haloalkoxygroup or alkylthio group represented by each of R^(a) to R^(e) mayinclude the same halogen atom (such as a fluorine atom or a chlorineatom), C₁₋₄alkyl group (such as a C₁₋₂alkyl group), fluoroC₁₋₄alkylgroup (such as a fluoroC₁₋₂alkyl group), C₁₋₄alkoxy group (such as aC₁₋₂alkoxy group), fluoroC₁₋₄alkoxy group (such as a fluoroC₁₋₂alkoxygroup) and C₁₋₄alkylthio group (such as a C₁₋₂alkylthio group) as thesubstituent of the group A.

The particularly preferred group A includes a mono- or di-substitutedaryl group (such as a mono- or di-substituted C₆₋₁₀aryl group), forexample, a phenyl group having substituent (s) at 2-position and/or4-position.

That is, the preferred one includes a group represented by the formula(2) in which each of R^(b), R^(d) and R^(e) is a hydrogen atom and atleast one of R^(a) and R^(c) is a halogen atom, an alkyl group, ahaloalkyl group, a hydroxyl group, an alkoxy group, a haloalkoxy group,a mercapto group or an alkylthio group [for example, a group representedby the formula (2) in which each of Rb, R^(d) and R^(e) is a hydrogenatom and the combination of R^(a) and R^(c) (R^(a), R^(C)) is (a halogenatom, a halogen atom), (an alkyl group, an alkyl group), (a hydroxylgroup, a hydroxyl group), (an alkoxy group, an alkoxy group), (an alkylgroup, a halogen atom), (a hydroxyl group, a halogen atom), (an alkoxygroup, a halogen atom), (a hydroxyl group, an alkyl group) or (an alkoxygroup, an alkyl group)]. Concretely, the group A is preferably a2,4-dihalophenyl group, a 2,4-diC₁₋₄alkylphenyl group, a2,4-dihydroxyphenyl group, a 2,4-diC₁₋₄alkoxyphenyl group, a2-C₁₋₄alkyl-4-halophenyl group, a 2-hydroxy-4-halophenyl group, a2-C₁₋₄alkoxy-4-halophenyl group, a 2-hydroxy-4-C₁₋₄alkylphenyl group, a2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl group, or the like.

In the formula (1), it is preferable that n be 0 or 1 (the group A benot essential) and particularly preferable that n be 1 (the formula (1)have the group A).

The heterocyclic ring represented by the ring B may be a nonaromaticheterocyclic ring or an aromatic heterocyclic ring or may be amonocyclic heterocyclic ring or a condensed heterocyclic ring. Theheterocyclic ring represented by the ring B is not particularly limitedto a specific one and may for example be a heterocyclic ring (e.g., anaromatic heterocyclic ring) containing at least one hetero atom selectedfrom the group consisting of a nitrogen atom (N), an oxygen atom (O) anda sulfur atom (S), as a constituent atom thereof. The number of heteroatoms is not particularly limited to a specific one and may for examplebe about 1 to 4 (preferably about 1 to 3, particularly about 1 to 2).

The monocyclic heterocyclic ring is, for example, a 5- to 8-memberedheterocyclic ring, preferably a 5- to 7-membered heterocyclic ring, andmore preferably a 5- or 6-membered heterocyclic ring.

The 5-membered monocyclic heterocyclic ring may include a heterocyclicring containing one hetero atom as a constituent atom thereof (e.g.,pyrrole, furan, and thiophene), a heterocyclic ring containing aplurality of (e.g., 2 to 3) hetero atoms as constituent atoms thereof(e.g., a heterocyclic ring containing a nitrogen atom, such asimidazole, pyrazole or triazole; a heterocyclic ring containing anoxygen atom and a nitrogen atom, such as oxazole, isoxazole oroxadiazole (or furazan); and a heterocyclic ring containing a sulfuratom and a nitrogen atom, such as triazole, isothiazole or thiadiazole),hydrogenated products of these rings, and others.

As the 6-membered heterocyclic ring, there may be mentioned aheterocyclic ring containing one hetero atom as a constituent atomthereof (e.g., pyridine and pyran), a heterocyclic ring containing aplurality of (e.g., 2 to 4) hetero atoms as constituent atoms thereof(e.g., a heterocyclic ring containing a nitrogen atom, such aspyridazine, pyrimidine, pyrazine, triazine or tetrazine), hydrogenatedproducts of these rings, and others.

The condensed heterocyclic ring may include a condensed ring (e.g., a 6to 15-membered ring, and preferably a 8 to 13-membered ring) containingthe monocyclic 5- to 8-membered heterocyclic ring, for example, acondensed ring of (i) a benzene ring, (ii) a C₄₋₈aliphatic carbocyclicring or a 5- to 8-membered heterocyclic ring containing at least anoxygen atom as a hetero atom, and (iii) a 5- to 8-membered heterocyclicring containing at least a nitrogen atom as a hetero atom [for example,a condensed ring of (i) a benzene ring, (ii) a cycloalkane ring (e.g., aC₄₋₈cycloalkane ring such as cyclohexane ring), a cycloalkene ring(e.g., a C₄₋₈cycloalkene ring such as cyclohexene ring) or a 5- or6-membered ring selected from the group consisting of a chroman ring, aisochroman ring, chromene ring and an isochromene ring, and (iii) apyrrole ring (e.g., indenopyrazole and chromenopyrazole); andhydrogenated product of these rings]. Adjacent two substituents of themonocyclic 5- to 8-membered heterocyclic ring may be bonded to eachother to form the condensed heterocyclic ring. Moreover, the condensedheterocyclic ring may be formed by bonding the substituent of the ring Aand the substituent on the monocyclic 5- to 8-membered heterocyclic ringto each other [in this case, n is 0 in the formula (1)].

The hetero atom (particularly a nitrogen atom) or carbon atom of thering B may have a substituent. The substituent may include an alkylgroup, a cycloalkyl group, an aryl group, an aralkyl group, an acylgroup, an amino group, an N-substituted amino group, and other groups.If necessary, the substituents may further have a substituent [e.g., ahalogen atom, a hydroxyl group, and an alkoxy group (a straight chain orbranched chain C₁₋₄alkoxy group)] to form a haloalkyl group, ahydroxyaryl group, an alkoxyaryl group, or the like. The amino group andthe N-substituted amino group are practically located at a carbon atomof the heterocyclic ring of the ring B.

The alkyl group, cycloalkyl group, aryl group and aralkyl group as thesubstituent of the ring B may include the same straight chain orbranched chain C₁₋₆alkyl group, C₃₋₁₀cycloalkyl group, C₆₋₁₀aryl groupand C₆₋₁₀arylC₁₋₆alkyl group as the group A, respectively.

The acyl group as the substituent of the ring B may include, forexample, formyl group, a straight chain or branched chainC₁₋₁₀alkyl-carbonyl group (preferably a C₁₋₆alkyl-carbonyl group, andmore preferably a C₁₋₄alkyl-carbonyl group) such as acetyl, propionyl orbutylyl group; a C₃₋₁₀cycloalkyl-carbonyl group such ascyclohexylcarbonyl group; a C₆₋₁₀aryl-carbonyl group such as benzoylgroup; and a C₆₋₁₀aryl-C₁₋₄alkylcarbonyl group such as benzylcarbonylgroup.

As the N-substituted amino group as the substituent of the ring B, theremay be mentioned the same N-monosubstituted amino group [for example, anN—C₁₋₆alkylamino group and an N—(C₁₋₆alkyl-carbonyl)amino group] andN,N-disubstituted amino group [for example, an N,N-diC₁₋₆alkylaminogroup and an N,N-di(C₁₋₆alkyl-carbonyl)amino group] as the substituentof the group A.

Examples of the haloalkyl group as the substituent of the ring B mayinclude the same straight chain or branched chain haloC₁₋₆alkyl group asthe group A. Moreover, as the substituent of the ring B, the hydroxyarylgroup may include a hydroxyC₆₋₁₀aryl group such as hydroxyphenyl orhydroxynaphthyl group; the alkoxyaryl group may include aC₁₋₆alkoxyC₆₋₁₀aryl group such as methoxyphenyl, methoxynaphthyl,ethoxyphenyl or ethoxynaphthyl group.

Among these substituents, an alkyl group, a haloalkyl group, acycloalkyl group, an aryl group, an aralkyl group, a hydroxyaryl group,an alkoxyaryl group, and an acyl group are preferred. As the alkylgroup, a C₁₋₄alkyl group such as methyl, ethyl, propyl or isopropylgroup is preferred. The preferred haloalkyl group includes ahaloC₁₋₄alkyl group [for example, a mono- to per-fluoroC₁₋₃alkyl group(e.g., a mono- to per-fluoroC₁₋₂alkyl group)] such as trihalomethylgroup. The cycloalkyl group preferably includes a C₃₋₆cycloalkyl groupsuch as cyclopropyl group. As the aryl group, a C₆₋₁₀aryl group such asphenyl group is preferred. As the aralkyl group, the preferred oneincludes a C₆₋₁₀arylC₁₋₄alkyl group (e.g., a C₆₋₁₀arylC₁₋₂alkyl group)such as benzyl group. The hydroxyaryl group preferably includes ahydroxyC₆₋₁₀aryl group such as hydroxyphenyl group. As the alkoxyarylgroup, a C₁₋₄alkoxyC₆₋₁₀aryl group (e.g., a C₁₋₂alkoxyC₆₋₁₀aryl group)such as methoxyphenyl group is preferred. The acyl group preferablyincludes a C₁₋₄alkyl-carbonyl group (e.g., a C₁₋₂alkyl-carbonyl group)such as acetyl group.

There is no particular limitation as to the position of the substituent.Depending on the species of the ring B, for example, the substituent maybe located at 1-, 2-, or 3-position to a nitrogen atom or may be locatedat 3- or 4-position to a sulfur atom or an oxygen atom. The position ofthe substituent practically contains at least 1-position and/or4-position.

The position of the ring B to be linked to the ring A and that to belinked to the linker L are not particularly limited. The ring A and thelinker L may bond to the ring B at adjacent position or non-adjacentposition (for example, 2,4-positions, 2,5-positions, 3,5-positions, or3,6-positions) and are practically located at 2,5-positions or3,5-positions with respect to a hetero atom constituting the ring B.

The preferred ring B includes a pyrrole ring, a furan ring, a thiophenering, an imidazole ring, a pyrazole ring, a thiazole ring, anisothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazolering, a pyridine ring, a pyrimidine ring, and a quinoline ring.Concretely, the ring B includes groups (linking units or joining units)represented by the following formulae (3-1) to (3-18).

In each one of the formulae (3-1) to (3-18), the left end and the rightend may be linked to the linker L and the ring A, respectively; or theleft end and the right end may be linked to the ring A and the linker L,respectively. Each one of these rings may have a substituent. That is,each hydrogen atom bonding to carbon atom and/or nitrogen atomconstituting the ring may be replaced with the above-exemplifiedsubstituent (for example, an alkyl group, a haloalkyl group, acycloalkyl group, an aryl group, an aralkyl group, and an acyl group).As the ring B with or without a substituent, the group represented byany one of the following formulae (3-a) to (3-p) is preferred.

In the formulae, Y represents a hydrogen atom, an alkyl group, ahaloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group, oran acyl group.

In each one of the formulae (3-a) to (3-p), it is preferable that theleft end and the right end be linked to the ring A and the linker L,respectively.

In the formulae (3-a), (3-b), (3-d), (3-f), (3-h), (3-i), (3-m) and(3-n), the alkyl group, haloalkyl group, cycloalkyl group, aryl group,aralkyl group and acyl group, each represented by the group Y, mayinclude the same groups as the substituent of the ring B, for example, aC₁₋₄alkyl group, a haloC₁₋₄alkyl group (e.g., a fluoroC₁₋₄alkyl group),a C₃₋₆cycloalkyl group, a C₆₋₁₀aryl group, a C₆₋₁₀arylC₁₋₄alkyl groupand C₁₋₄alkyl-carbonyl group, respectively. The group Y is practicallyan alkyl group or an acyl group.

The further preferred ring B may include a 5-membered heterocyclic ringcontaining two or more hetero atoms as constituent atoms thereof,wherein at least one hetero atom is a nitrogen atom; particularly, athiazole ring, isothiazole ring or pyrazole ring which may have asubstituent (such as an alkyl group or an acyl group) [for example, aring represented by the formula (3-a), (3-b) or (3-f)].

In the formula (1), the aromatic ring represented by the ring C is notparticularly limited to a specific one, and may be a carbocyclic ring ora heterocyclic ring.

The aromatic carbocyclic ring may be a monocyclic or condensed cyclicarene ring (for example, a condensed bi- to tetra-cyclic arene ring).The aromatic carbocyclic ring may include, for example, a C₆₋₂₄arenering (preferably a C₆₋₂₀arene ring, and more preferably a C₆₋₁₈arenering) such as benzene, indan, indene, naphthalene, fluorene,phenanthrene or anthracene.

The aromatic heterocyclic ring is not particularly limited to a specificone and usually contains at least one hetero atom selected from thegroup consisting of a nitrogen atom (N), an oxygen atom (O) and a sulfuratom (S), as a constituent atom thereof. The aromatic heterocyclic ringmay be a non-condensed ring (a monocyclic heterocyclic ring) or may be acondensed ring (a condensed ring of a heterocyclic ring and aheterocyclic ring, a condensed ring of a carbocyclic ring and aheterocyclic ring).

The non-condensed ring may include a 5- to 8-membered heterocyclic ring,preferably a 5- to 7-membered heterocyclic ring, and more preferably a5- or 6-membered heterocyclic ring. As representative examples of thenon-condensed ring, there may be mentioned a 5- or 6-membered ringcontaining a nitrogen atom as a hetero atom, e.g., pyrrole, imidazole,pyrazole, triazole, pyridine, pyridazine, pyrimidine, pyrazine,triazine, and tetrazine; a 5- or 6-membered ring containing an oxygenatom as a hetero atom, e.g., furan; a 5- or 6-membered ring containing asulfur atom as a hetero atom, e.g., thiophene; a 5- or 6-membered ringcontaining a nitrogen atom and an oxygen atom as hetero atoms, e.g.,oxazole, isoxazole, and oxazine; and a 5- or 6-membered ring containinga nitrogen atom and a sulfur atom as hetero atoms, e.g., triazole,isothiazole, and thiazine.

As the condensed ring, there may be mentioned a condensed ring (forexample, a 6 to 15-membered ring, and preferably a 8 to 13-memberedring) containing at least a 5- to 8-membered monocyclic heterocyclicring (for example, a 5- to 7-membered heterocyclic ring, andparticularly a 5- or 6-membered heterocyclic ring). Specifically, thecondensed ring may include a condensed ring containing a 5- or6-membered monocyclic heterocyclic ring having a nitrogen atom as ahetero atom [for example, a bicyclic condensed ring such as indole,indoline, isoindole, isoindoline, indolizine, indazole, benzimidazole,benzotriazole, purine, quinoline, isoquinoline, quinolizine, cinnoline,quinazoline, quinoxaline, phthalazine, naphthyridine or pteridine; and atricyclic condensed ring such as carbazole, acridine, phenazine,benzocinnoline (or phenazone), benzopyrroloimidazole,benzimidazopyridine or benzimidazoazepine], a condensed ring containinga 5- or 6-membered monocyclic heterocyclic ring having an oxygen atom asa hetero atom [for example, a bicyclic condensed ring such asbenzofuran, isobenzofuran, coumaran, coumarin, chromene, isochromene,chroman, isochroman or an alkylenedioxybenzene (aC₁₋₄alkylenedioxybenzene such as methylenedioxybenzene); and a tricycliccondensed ring such as dibenzofuran or xanthene], a condensed ringcontaining a 5- or 6-membered monocyclic heterocyclic ring having asulfur atom as a hetero atom [for example, a bicyclic condensed ringsuch as benzothiophene (or thionaphthene) or an alkylenedithiobenzene (aC₁₋₄alkylenedithiobenzene such as methylenedithiobenzene); and atricyclic condensed ring such as dibenzothiopyran or thianthrene], acondensed ring containing a 5- or 6-membered monocyclic heterocyclicring having a nitrogen atom and an oxygen atom as hetero atoms [forexample, a bicyclic condensed ring such as benzoxazole; and a tricycliccondensed ring such as phenoxazine or oxadiazafluorene (orbenzimidazomorpholine)], a condensed ring containing a 5- or 6-memberedmonocyclic heterocyclic ring having a nitrogen atom and a sulfur atom ashetero atoms [for example, a bicyclic condensed ring such asbenzothiazoline or benzothiazole; and a tricyclic condensed ring such asphenothiazine or thiadiazafluorene], and a condensed ring containing a5- or 6-membered monocyclic heterocyclic ring having an oxygen atom anda sulfur atom as hetero atoms [for example, a tricyclic condensed ringsuch as phenoxathiin ring]; or hydrogenated products of these rings.Among these condensed heterocyclic rings, the condensed ring practicallyincludes a condensed ring containing a benzene ring and a heterocyclicring (e.g., a 5 to 15-membered ring, and preferably a 5 to 10-memberedring) having at least one hetero atom selected from the group consistingof a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S) [forexample, a bicyclic condensed ring of a benzene ring and a 5- to8-membered monocyclic heterocyclic ring, and a condensed ring of abenzene ring and a 6- to 15-membered (e.g., 7- to 13-membered,preferably 8- to 10-membered) bicyclic heterocyclic ring (e.g., atricyclic condensed ring of a benzene ring and two 5- to 8-memberedmonocyclic heterocyclic rings which may be the same or different fromeach other)].

The ring C may have a substituent. When the ring C is a monocyclic arenering (for example, a benzene ring), the ring C practically has asubstituent from the viewpoint of the pharmacological activity.Specifically, in many cases, the ring C is a monocyclic arene ringhaving a substituent, a condensed cyclic arene ring which may have asubstituent, or a monocyclic or condensed cyclic heterocyclic ring whichmay have a substituent.

The substituent may include a halogen atom, an alkyl group, a cycloalkylgroup, an aryl group, a hydroxyl group, an alkoxy group, a carboxylgroup, an acyl group, a carbamoyl group, an N-substituted carbamoylgroup, a dihydroxyboryl group, a mercapto group, an alkylthio group, asulfonic acid group, an amino group, an N-substituted amino group, acyano group, a nitro group, and a heterocyclic group. If necessary, thesubstituent may further have a substituent [e.g., a halogen atom, anaryl group (such as a C₆₋₁₀aryl group), a hydroxyl group, an alkoxygroup (such as a straight chain or branched chain C₁₋₄alkoxy group), amercapto group, and an alkylthio group (such as a straight chain orbranched chain C₁₋₄alkylthio group)] to form a haloalkyl group, ahaloalkoxy group, an aralkyl group, an aryloxy group, an aralkyloxygroup, a hydroxyalkyl group, an alkoxyalkyl group, an alkoxycarbonylgroup, a mercaptoalkyl group, an alkylthioalkyl group, or the like.

The halogen atom, alkyl group, cycloalkyl group, aryl group, alkoxygroup and acyl group, as the substituent of the ring C, may include thesame halogen atom (such as a fluorine atom or a chlorine atom), straightchain or branched chain C₁₋₆alkyl group, C₃₋₁₀cycloalkyl group,C₆₋₁₀aryl group, C₁₋₆alkoxy group and C₁₋₆alkyl-carbonyl group,respectively, as the substituent on the group A or the ring B.

The N-substituted carbamoyl group as the substituent of the ring C mayinclude an N-monoC₁₋₆alkylcarbamoyl group, an N-monoC₁₋₆acyl-carbamoylgroup, an N,N-diC₁₋₆alkylcarbamoyl group, and anN,N-diC₁₋₆acyl-carbamoyl group.

The alkylthio group as the substituent of the ring C may include thesame straight chain or branched chain C₁₋₆alkylthio group (preferably aC₁₋₄alkylthio group) as the substituent of the group A.

The N-substituted amino group as the substituent of the ring C mayinclude the same N-monosubstituted amino group [for example, anN—C₁₋₆alkylamino group and an N—(C₁₋₆alkyl-carbonyl)amino group] andN,N-disubstituted amino group [for example, an N,N-diC₁₋₆alkylaminogroup and an N,N-di(C₁₋₆alkyl-carbonyl)amino group] as the substituentof the group A.

The heterocyclic group as the substituent of the ring C may includevarious heterocyclic groups, each containing an aromatic or nonaromatic5- to 8-membered heterocyclic ring (for example, a 5 to 7-membered ring,and preferably a 5- or 6-membered ring); for example, a group containinga 5- or 6-membered heterocyclic ring having at least one hetero atomselected from the group consisting of a nitrogen atom, an oxygen atom, asulfur atom and a boron atom [e.g., a 5- or 6-membered heterocyclicgroup having a nitrogen atom and an oxygen atom as hetero atoms, such asa morpholyl group (e.g., 4-morpholyl group); and a 5- or 6-memberedheterocyclic group containing a boron atom and an oxygen atom as heteroatoms, such as 1,3,2-dioxaborinan-2-yl group].

The haloalkyl group, haloalkoxy group and aralkyl group (arylalkylgroup) as the substituent of the ring C may include the same straightchain or branched chain haloC₁₋₆alkyl group, (preferably a haloC₁₋₄alkylgroup), straight chain or branched chain haloC₁₋₆alkoxy group(preferably, e.g., a mono- to per-fluoroC₁₋₄alkoxy group such asdifluoromethyloxy or trifluoromethyloxy group, and chloroC₁₋₄alkoxygroups corresponding to these fluoroC₁₋₄alkoxy groups) andC₆₋₁₀arylC₁₋₆alkyl group (preferably a C₆₋₁₀arylC₁₋₄alkyl group),respectively, as substituent on the group A or the ring B.

The aryloxy group as the substituent of the ring C may include a C₆₋₁₀aryloxy group such as phenyloxy or naphthyloxy group; the aralkyloxygroup as the substituent of the ring C may include aC₆₋₁₀arylC₁₋₆alkyloxy group (preferably a C₆₋₁₀arylC₁₋₄alkyloxy group)such as benzyloxy or phenethyloxy group.

The hydroxyalkyl group as the substituent of the ring C may include ahydroxyl-straight chain or branched chain C₁₋₆alkyl group (preferably ahydroxyC₁₋₄alkyl group) such as hydroxymethyl, 2-hydroxyethyl or3-hydroxypropyl group.

The alkoxyalkyl group as the substituent of the ring C may include astraight chain or branched chain C₁₋₆alkoxyC₁₋₆alkyl group (preferably aC₁₋₄alkoxyC₁₋₄alkyl group) such as methoxymethyl, methoxyethyl,ethoxymethyl or ethoxyethyl group.

The alkoxycarbonyl group as the substituent of the ring C may include astraight chain or branched chain C₁₋₆alkoxy-carbonyl group (preferably,e.g., a C₁₋₄alkoxy-carbonyl group) such as methoxycarbonyl orethoxycarbonyl group.

The mercaptoalkyl group as the substituent of the ring C may include amercapto-straight chain or branched chain C₁₋₆alkyl group correspondingto the hydroxyalkyl group. The alkylthioalkyl group may include astraight chain or branched chain C₁₋₆alkylthioC₁₋₆alkyl groupcorresponding to the alkoxyalkyl group.

The monocyclic or condensed cyclic arene ring having a substituent mayinclude, for example, an arene ring (a C₆₋₂₄arene ring such as benzeneor naphthalene) having at least one substituent selected from the groupconsisting of a halogen atom, an alkyl group, a haloalkyl group, acycloalkyl group, an aryl group, an aralkyl group, a hydroxyl group, analkoxy group, a haloalkoxy group, an aryloxy group, an aralkyloxy group,a dihydroxyboryl group, a carboxyl group, an alkoxycarbonyl group, amercapto group, an alkylthio group, a nitro group, an amino group, anN-substituted amino group and a heterocyclic group.

The combination of the substituents is not particularly limited to aspecific one. For the disubstituted arene ring, two substituents may bethe same or different from each other and may for example be selectedfrom the group consisting of a halogen atom, an alkyl group, a hydroxylgroup, an alkoxy group, a haloalkoxy group, a dihydroxyboryl group and anitro group. For the trisubstituted arene ring, three substituents maybe the same or different from one another and may for example beselected from the group consisting of a halogen atom, an alkyl group, ahydroxyl group and an alkoxy group. There is no particular limitation asto the position of the substituent. For example, for a monosubstitutedbenzene, the substituent may be located at 2-, 3-, or 4-position; for adisubstituted benzene, the substituents may be located at 2,3-, 2,4-,2,5-, 3,4-, or 3,5-positions; for a trisubstituted benzene, thesubstituents may be located at 2,3,4- or 3,4,5-positions.

The monocyclic heterocyclic ring having a substituent may include a 5-to 8-membered heterocyclic ring having at least one substituent selectedfrom the group consisting of a hydroxyl group, an alkoxy group (e.g., aC₁₋₆alkoxy group), a mercapto group and an alkylthio group (e.g., aC₁₋₆alkylthio group) {for example, a 5- or 6-membered heterocyclic ringcontaining at least one hetero atom selected from the group consistingof a nitrogen atom, an oxygen atom and a sulfur atom [e.g., analkoxypyridine (e.g., a C₁₋₄alkoxypyridine such as 2-methoxypyridine)]}.

The condensed heterocyclic ring having a substituent may include theabove-mentioned condensed heterocyclic ring having at least onesubstituent selected from the group consisting of an alkyl group, ahydroxyalkyl group, an alkoxyalkyl group, a hydroxyl group, an alkoxygroup and an acyl group.

The preferred ring C includes a monocyclic or condensed ring having atleast a benzene skeleton and may for example be any one of the followingformulae (4-a) to (4-c):

wherein Z¹ represents a halogen atom, an alkyl group, a hydroxyl group,an alkoxy group, a mercapto group, an alkylthio group, anN-alkyl-substituted amino group or an N-acyl-substituted amino group; Z²represents an alkyl group, a hydroxyalkyl group, an alkoxyalkyl group oran acyl group; Z³ represents an alkyl group, a hydroxyl group, an alkoxygroup or an acyl group; the ring C¹ represents a C₁₋₆₋₁₀arene ring; thering C² represents a 5- to 8-membered heterocyclic ring containing G¹and G², the ring containing at least one hetero atom selected from thegroup consisting of a nitrogen atom (N), an oxygen atom (O) and a sulfuratom (S) as a constituent atom thereof; the ring C³ represents a 5- to8-membered heterocyclic ring containing G⁴ of the ring adjacent thereto,the ring C³ containing at least one hetero atom selected from the groupconsisting of a nitrogen atom (N), an oxygen atom (O) and a sulfur atom(S) as a constituent atom thereof; G¹ to G³ each represent a nitrogenatom (N), an oxygen atom (O), a sulfur atom (S), NH, CH or CH₂ dependingon the aromaticity or nonaromaticity of the ring C² or that of the5-membered ring adjacent to the ring C³; G⁴ represents a nitrogen atom(N), a carbon atom (C) or CH depending on the aromaticity ornonaromaticity of the 5-membered ring adjacent to the ring C³; p is aninteger of 1 to 5, and q is an integer of 0 to 6.

In the formula (4-c), the chemical bond represented as follows:

represents a single bond or a double bond.

In the formula (4-a), the arene ring represented by the ring C¹ mayinclude a C₆₋₁₀arene ring such as benzene or naphthalene.

The halogen atom, alkyl group, alkoxy group, alkylthio group,N-alkyl-substituted amino group and N-acyl-substituted amino group, eachrepresented by Z¹, may include the halogen atom (such as a fluorine atomor a chlorine atom), C₁₋₆alkyl group, C₁₋₆alkoxy group, C₁₋₆alkylthiogroup, N—C₁₋₆alkyl-substituted amino group andN—(C₁₋₆alkyl-carbonyl)substituted amino group, respectively, eachexemplified as the substituent on the ring C. When p is an integer ofnot less than 2, the species of Z¹ may be the same or different fromeach other.

The coefficient p (the number p) of Z¹ is about 1 to 5, preferably about1 to 4, and more preferably about 1 to 3 (e.g., 1 to 2). Moreover, thereis no particular limitation as to the position of the substituent Z¹.For example, when the ring C¹ is a benzene ring, the position of thesubstituent Z¹ may be 2-, 3-, 4-, or 5-position in the ring, and ispreferably at least 3- and/or 4-position (in particular, at least4-position) in the ring.

The group represented by the formula (4-a) preferably includes, forexample, a group represented by the following formula (4-a2):

wherein Z^(a) represents a hydroxyl group, an alkoxy group, a mercaptogroup, an alkylthio group, an N,N-dialkylamino group or anN,N-diacylamino group; Z^(b) represents a hydrogen atom, an alkyl group,a hydroxyl group or an alkoxy group.

In the formula (4-a2), the alkoxy group, alkylthio group,N,N-dialkylamino group or N,N-diacylamino group represented by Z^(a) mayinclude the same C₁₋₆alkoxy group (preferably a C₁₋₄alkoxy group),C₁₋₆alkylthio group (preferably a C₁₋₄alkylthio group),N,N-diC₁₋₆alkylamino group (preferably an N,N-diC₁₋₄alkylamino group) orN,N-di(C₁₋₆alkyl-carbonyl)amino group [preferably anN,N-di(C₁₋₄alkyl-carbonyl)amino group] as the above-exemplified group.The alkyl group or alkoxy group represented by Z^(b) may include thesame C₁₋₆alkyl group (preferably a C₁₋₄alkyl group) or C₁₋₆alkoxy group(preferably a C₁₋₄alkoxy group) as the above-exemplified group.

When Z^(a) is a hydroxyl group or an alkoxy group, Z^(b) is practicallyan alkyl group, a hydroxyl group or an alkoxy group.

In the formula (4-b), the ring C² is a 5- to 8-membered heterocyclicring (for example, a 5- to 7-membered heterocyclic ring, and preferablya 5- or 6-membered heterocyclic ring) containing G¹ and G² asconstituent atoms thereof, and is usually a heterocyclic ring containingat least one hetero atom selected from the group consisting of anitrogen atom (N), an oxygen atom (O) and a sulfur atom (S) as aconstituent atom thereof. The ring C² may for example be a ring (aheterocyclic ring) of the above-exemplified bicyclic condensedheterocyclic ring [that is, a residue obtained by removing a benzenering from a condensed ring of the benzene ring and a heterocyclic ringcontaining at least one hetero atom selected from the group consistingof a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S) as aconstituent atom thereof (for example, a nitrogen-atom-containingheterocyclic ring such as indole, indoline, isoindole, isoindoline,indazole, benzimidazole, benzotriazole, quinoline, isoquinoline,cinnoline, quinazoline, quinoxaline or phthalazine; and anoxygen-atom-containing heterocyclic ring such as benzofuran,isobenzofuran, coumaran, coumarin, chromene, isochromene, chroman,isochroman or an alkylenedioxybenzene)].

In the formula (4-c), the ring C³ is a 5 to 8-membered ring (e.g., a 5to 7-membered ring) containing G⁴ as a constituent atom thereof, and isusually a heterocyclic ring containing at least one hetero atom selectedfrom the group consisting of a nitrogen atom (N), an oxygen atom (O) anda sulfur atom (S) as a constituent atom thereof. The ring C³ may forexample be a ring of the above-exemplified tricyclic condensedheterocyclic ring {e.g., a residue obtained by removing a benzene ringand a 5-membered monocyclic ring adjacent to the benzene ring from atricyclic condensed heterocyclic ring, having a benzene skeleton at anend thereof, of the benzene ring, the 5-membered monocyclic carbocyclicor heterocyclic ring and a 5- to 8-membered heterocyclic ring [forexample, a condensed ring of a benzene ring, an imidazole ring and aring selected from the group consisting of a pyrrole ring, a pyridinering, an azepine ring and a morpholine ring (e.g.,benzopyrroloimidazole, benzimidazopyridine, benzimidazoazepine, andbenzimidazomorpholine), or hydrogenated products of these rings]].

The alkyl group or acyl group represented by Z² and Z³ may include theC₁₋₆alkyl group (preferably a C₁₋₄alkyl group) or C₁₋₆alkyl-carbonylgroup (preferably a C₁₋₄alkyl-carbonyl group) exemplified as thesubstituent of the ring C. The hydroxyalkyl group or alkoxyalkyl grouprepresented by Z² may include the hydroxyC₁₋₆alkyl group (preferably ahydroxyC₁₋₄alkyl group) or C₁₋₆alkoxyC₁₋₆alkyl group (preferably aC₁₋₄alkoxyC₁₋₄alkyl group) exemplified as the substituent of the ring C.The alkoxy group represented by Z³ may include the C₁₋₆alkoxy group(preferably a C₁₋₄alkoxy group) exemplified as the substituent of thering C. Each one of these substituents Z² and Z³ is practically an alkylgroup, an acyl group, or the like. When q is an integer of not less than2, the species of the substituent Z² (or Z³) may be the same ordifferent from each other.

The coefficient q of Z² (or Z³) is, for example, 0 to 6, preferablyabout 0 to 4, more preferably about 0 to 3, and particularly about 0 to2.

The group represented by the formula (4-b) may include a groupcomprising a condensed ring of a benzene ring and a 5- to 8-memberedmonocyclic heterocyclic ring containing at least one hetero atomselected from the group consisting of a nitrogen atom (N), an oxygenatom (O) and a sulfur atom (S) as a constituent atom thereof, forexample, a condensed ring group of a 5- or 6-membered heterocyclic ringcontaining an oxygen atom as a hetero atom and a benzene ring, such as abenzofuryl group (e.g., benzofuran-5-yl group), a coumaryl group (e.g.,coumaran-5-yl group), a coumarinyl group (e.g., coumarin-5-yl group), oran alkylenedioxyphenyl group (e.g., a C₁₋₄alkylenedioxyphenyl group suchas 3,4-methylenedioxyphenyl group); a condensed ring group of a 5- or6-membered heterocyclic ring containing a nitrogen atom as a hetero atomand a benzene ring, such as an indolyl group [e.g., indol-4-(or 5-, 6-,7-) yl group], an alkylindolyl group [e.g., a C₁₋₄alkylindolyl groupsuch as 1-methylindol-5-(or 6-)yl group], an indazolyl group [e.g.,1H-(or 2H-)indazol-5-(or 6-)yl group], an alkylindazolyl group [e.g., aC₁₋₄alkylindazolyl group such as 1-methyl (or 1-ethyl)-1H-indazol-5-ylgroup, 1-methyl (or 1-ethyl)-1H-indazol-6-yl group or 2-methyl (or2-ethyl)-2H-indazol-5-yl group], a benzimidazolyl group [e.g.,benzimidazol-5-yl group], an alkylbenzimidazolyl group [e.g., a mono- ordi-C₁₋₄alkylbenzimidazolyl group such as 1-methyl (or 1-ethyl, 1-propyl,1-isopropyl)benzimidazol-5-yl group, 1,2-dimethylbenzimidazol-5-ylgroup, 1-methyl-2-ethyl-benzimidazol-5-yl group or1-ethyl-2-methyl-benzimidazol-5-yl group], a benzotriazolyl group [e.g.,benzotriazol-5-yl group], an alkylbenzotriazolyl group [e.g., aC₁₋₄alkylbenzotriazolyl group such as 1-methyl (or1-ethyl]benzotriazol-5-yl group], a quinolyl group [e.g., quinolin-6-ylgroup], a quinoxalinyl group [e.g., quinoxalin-6-yl group], or analkylquinoxalinyl group [e.g., a mono- or di-C₁₋₄alkylquinoxalinyl groupsuch as 2,3-dimethylquinoxalin-6-yl group]; a condensed ring group of a5- or 6-membered heterocyclic ring containing a nitrogen atom and anoxygen atom as hetero atoms and a benzene ring, such as a benzoxazolylgroup [e.g., benzoxazol-6-yl group] or a dihydrobenzoxazinyl group[e.g., 2,3-dihydro-1,4-benzoxazin-6-yl group]; and others.

The group represented by the formula (4-c) may include a condensed ringgroup of a benzene ring, a 5-membered monocyclic heterocyclic ringcontaining at least one hetero atom selected from the group consistingof a nitrogen atom (N), an oxygen atom (O) and a sulfur atom (S), and a5- to 8-membered monocyclic heterocyclic ring containing at least onehetero atom selected from the group consisting of a nitrogen atom (N),an oxygen atom (O) and a sulfur atom (S), for example, a condensed ringgroup of a benzene ring, an imidazole ring, and a ring selected from thegroup consisting of a pyrrole ring, a pyridine ring, an azepine ring anda morpholine ring {e.g., a benzopyrroloimidazolyl group or a groupcontaining a hydrogenated product thereof such as2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazolyl group; abenzimidazopyridyl group or a group containing a hydrogenated productthereof such as 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridyl group;a benzimidazoazepinyl group or a group containing a hydrogenated productthereof such as 7,8,9,10-tetrahydro-6H-benzo[4,5]imidazo[1,2-a]azepinylgroup; and a 2-oxa-4-a, 9-diazafluorenyl group or a group containing ahydrogenated product thereof such as3,4-dihydro-1H-2-oxa-4a,9-diazafluorenyl group}.

Among the groups represented by the formula (4-b) or (4-c), a grouprepresented by the following formula (4-b2) or (4-c2) is preferred.

In the formulae, the ring C² represents a 5- to 8-membered heterocyclicring (e.g., a 5- to 7-membered heterocyclic ring, and preferably a 5- or6-membered heterocyclic ring) having G¹ and G², and contains at leastone (e.g., about 1 to 3) hetero atom selected from the group consistingof a nitrogen atom (N) and an oxygen atom (O) as a constituent atomthereof; the ring C³ represents a 5- to 8-membered heterocyclic ring(e.g., a 5- to 7-membered heterocyclic ring) having G⁴ of the ringadjacent thereto, and contains at least one hetero atom (e.g., about 1to 2) selected from the group consisting of a nitrogen atom (N) and anoxygen atom (O) as a constituent atom thereof; G² represents an oxygenatom (O), a nitrogen atom (N) or NH depending on the aromaticity ornonaromaticity of the ring C²; G⁴ represents a nitrogen atom (N); andthe group Z², the group Z, G¹, G³ and q have the same meanings asdefined above.

In the formula (4-c2), the broken line indicates that the 5-memberedring which is adjacent to the ring C³ and contains G³ and G⁴ may be anaromatic ring or a nonaromatic (aliphatic) ring.

Concretely, the group represented by the formula (4-b2) or (4-c2)include groups represented by any one of following formulae (4-b3) to(4-b6), (4-c2) and (4-c3):

wherein G⁵ represents N, NH, S, O, CH or CH₂; G⁶ represents N, NH, S orO; G⁷ represents N or NH; G⁸ represents N, NH, S or O; G⁹ to G¹¹ eachrepresent N or NH; G¹² represents CH or N; G¹³ represents N; and G¹⁴represents NH, O, S or CH₂.

Each one of the groups represented by the formulae (4-b3) to (4-b6),(4-c2) and (4-c3) may have a substituent. That is, each hydrogen atombonding to carbon atom and/or nitrogen atom constituting the ring may bereplaced with the above-exemplified substituent (for example, an alkylgroup and an acyl group).

As the group included in the formula (4-b2), a group represented by theformula (4-b2) in which G¹ is a nitrogen atom (N), CH or CH₂ ispreferred. As the group included in the formula (4-c2), a grouprepresented by the formula in which G³ is a nitrogen atom (N) or NH ispreferred. In particular, it is preferable that the group be representedby any one of the following formulae (5-a) to (5-k):

wherein Z represents a hydrogen atom, an alkyl group, or an acyl group.

In the formulae (5-a) to (5-e), the alkyl group and the acyl group, eachrepresented by Z may include the C₁₋₆alkyl group (preferably a C₁₋₄alkylgroup) and the C₁₋₆alkyl-carbonyl group (preferably a C₁₋₄alkyl-carbonylgroup), respectively, exemplified as the substituent of the ring C. Inthe formula (5-a), the species of two substituents Z may be the same ordifferent from each other.

In the formula (1), the linker represented by L is not particularlylimited to a specific one as far as the ring B and the ring C can belinked (or joined) through the linker. For example, the linker has amain chain containing about 3 to 5 (particularly 4 to 5) atoms, eachselected from the group consisting of a carbon atom (C), a nitrogen atom(N), an oxygen atom (O) and a sulfur atom (S). The main chain of thelinker usually comprises at least one carbon atom and at least onehetero atom selected from the group consisting of a nitrogen atom, anoxygen atom and a sulfur atom. Moreover, each hydrogen atom bonding tothe carbon atom of the main chain may be replaced with a group selectedfrom the group consisting of an oxygen atom (or oxo group or group ═O),a sulfur atom (or thioxo group or group ═S), an alkyl group and an acylgroup; each hydrogen atom bonding to the nitrogen atom of the main chainmay be replaced with a group selected from the group consisting of analkyl group and an acyl group. The bonding manner of the atoms of themain chain is not particularly limited to a specific one. For example,the linker may include a linker containing at least one chemical bondselected from the group consisting of an amide bond, a urethane bond, athioamide bond, a thiourethane bond and an ether bond. Concretely, thelinker may contain at least any one of basic skeletons (basic units)represented by following formulae (1-a) to (1-i):

In these basic skeletons (1-a) to (1-i), the hydrogen atom of the —NH—group may be replaced with a group such as an alkyl group or an acylgroup. The alkyl group may include the same straight chain or branchedchain C₁₋₆alkyl group (preferably a C₁₋₄alkyl group) as the group A. Theacyl group may include the same straight chain or branched chainC₁₋₆alkyl-carbonyl group (preferably a C₁₋₄alkyl-carbonyl group) as thesubstituent of the ring B.

Among these linkers, representative linkers are shown in Table 1.

TABLE 1 Basic skeltons Representative examples

  (1-a)

  (1-a1)

  (1-a2)

  (1-a3)

  (1-a4)

  (1-a5)

  (1-a6)

  (1-b)

  (1-b1)

  (1-b2)

  (1-c)

  (1-c1)

  (1-c2)

  (1-c3)

  (1-d)

  (1-d1)

  (1-d2)

  (1-d3)

  (1-e)

  (1-e1)

  (1-e2)

  (1-f)

  (1-f1) —O—   (1-g)

  (1-g1)

  (1-g2)

  (1-h)

  (1-h1)

  (1-i)

  (1-i1)

In the formulae shown in Table 1, X¹ represents an alkyl group, and X²represents an alkyl group or an acyl group. The alkyl group representedby X¹ or X² may include the same C₁₋₄alkyl group (e.g., a C₁₋₂alkylgroup) as the above-exemplified group; the acyl group represented by X²may include the same C₁₋₄alkyl-carbonyl group (e.g., aC₁₋₂alkyl-carbonyl group) as the above-exemplified group.

In the basic skeleton and representative linker shown in Table 1, theleft end and the right end may be linked to the ring C and the ring B,respectively. It is preferable that the left end and the right end belinked to the ring B and the ring C, respectively.

Among these linkers, a linker containing any one of the basic skeletonsrepresented by the formulae (1-a) to (1-c) is preferred. In particular,a linker containing the urethane bond (—NHC(O)O— or —OC(O)NH—)represented by the formula (1-a) [for example, a linker represented byeach of the formulae (1-a1) to (1-a6)] is preferred.

When the linker L is a linker represented by the formula (1-a1), in manycases the group A is a group other than 2-methylaminopyrimidin-4-ylgroup and the ring C is a ring other than 9-fluorenyl group. When thelinker L is a linker represented by the formula (1-a2) in which X¹ ismethyl group and the ring C is a benzene ring having a halogen atom as asubstituent, the ring B is a ring other than an isoxazole-diyl group(particularly, 3,4-isoxazole-diyl group) in many cases.

The heterocyclic compound represented by the formula (1) or the saltthereof according to the present invention is novel. Moreover, theheterocyclic compound having any combination of the groups (orbiological equivalents) exemplified in each item of the group A, thering B, the linker L and the ring C, or the pharmaceutically (orphysiologically) acceptable salt thereof is novel as a p27^(Kip1)ubiquitination inhibitor (or degradation inhibitor). Further, theheterocyclic compound having any combination of the groups (orbiological equivalents) exemplified in each item of the group A, thering B, the linker L and the ring C, or the pharmaceutically (orphysiologically) acceptable salt thereof [with the proviso that when thelinker L is a linker represented by the formula (1-a2) in which X¹ ismethyl group and the ring C is a benzene ring having a halogen atom as asubstituent, the ring B is a ring other than an isoxazole-diyl group(particularly, 3,4-isoxazole-diyl group)] is novel as a preventingand/or treating agent for a cell proliferative disease.

The compound represented by the formula (1) or the salt thereof is notparticularly limited to a specific one as far as the compound or thesalt thereof is the compound having any combination of the groupsexemplified in each item of the group A, the ring B, the linker L andthe ring C or the salt thereof; for example, from the viewpoint of thebinding property to the Skp2, the ability to inhibit p27^(Kip1)ubiquitination, the ability to inhibit p27^(Kip1) degradation, theability to inhibit cell proliferation, and the ability to induceapoptosis, the following compound or a salt thereof is preferred:

(1-1) a compound in which the linker L contains the basic skeleton ofthe formula (1-a) [for example, the compound (1) in which the linker Lis any one of the formulae (1-a1) to (1-a6), the group A is an arylgroup having a substituent (e.g., a group represented by the formula(2)), the ring B is a thiazole, isothiazole or pyrazole ring which mayhave a substituent, and the ring C is any one of the formulae (4-a) to(4-c)] or a salt thereof;(1-2) a compound in which the linker L contains the basic skeleton ofthe formula (1-b) [for example, the compound (1) in which the linker Lis the formula (1-b1) or (1-b2), the group A is an aryl group having asubstituent (e.g., a group represented by the formula (2)), the ring Bis a thiazole ring, pyrazole ring or furan ring which may have asubstituent, and the ring C is an aryl group represented by the formula(4-a) or a heterocyclic group represented by the formula (4-b) or(4-b2)] or a salt thereof;(1-3) a compound in which the linker L contains the basic skeleton ofthe formula (1-c) [for example, the compound (1) in which the linker Lis any one of the formulae (1-c1) to (1-c3), the ring A is an aryl grouphaving no substituent, an aryl group having a substituent (e.g., a grouprepresented by the formula (2)) or a heterocyclic group having asubstituent (e.g., a 5- to 8-membered heterocyclic group containing atleast a nitrogen atom as a hetero atom, such as pyridyl group), the ringB is a thiazole ring, isothiazole ring, pyrazole ring, pyrrole ring,imidazole ring or oxazole ring which may have a substituent, and thering C is an aryl group represented by the formula (4-a) (wherein Z¹ maybe a boronic acid group) or a heterocyclic group represented by theformula (4-b) or (4-b2)] or a salt thereof;(1-4) a compound in which the linker L contains the basic skeleton ofthe formula (1-d) [for example, the compound (1) in which the linker Lis anyone of the formulae (1-d1) to (1-d3), the group A is an aryl grouphaving a substituent (e.g., a group represented by the formula (2)), thering B is a thiazole ring or pyrazole ring which may have a substituent,and the ring C is an aryl group represented by the formula (4-a)] or asalt thereof;(1-5) a compound in which the linker L contains the basic skeleton ofthe formula (1-e) [for example, the compound (1) in which the linker Lis the formula (1-e1) or (1-e2), the group A is an aryl group havingsubstituent (e.g., a group represented by the formula (2)), the ring Bis a thiazole ring or pyrazole ring which may have a substituent, andthe ring C is an aryl group represented by the formula (4-a)] or a saltthereof;(1-6) a compound in which the linker contains the basic skeleton of theformula (1-g) [for example, the compound (1) in which the linker L isthe formula (1-g1) or (1-g2), the group A is an aryl group having asubstituent (e.g., a group represented by the formula (2)), the ring Bis a thiazole ring or pyrazole ring which may have a substituent, andthe ring C is an aryl group represented by the formula (4-a)] or a saltthereof; and(1-7) a compound in which the linker contains the basic skeleton of theformula (1-h) [for example, the compound (1) in which the linker L isthe formula (1-h1), the group A is aryl group having a substituent(e.g., a group represented by the formula (2)), the ring B is a thiazolering or pyrazole ring which may have a substituent, and the ring C is anaryl group represented by the formula (4-a)].

As the compound represented by the formula (1) or the salt thereof, acompound represented by any one of the following formulae (6-a) to (6-c)or a salt thereof is preferred, in particular, from the viewpoint of theability to inhibit p27^(Kip1) degradation and the ability to induceapoptosis.

In the formulae, R¹ and R² are the same or different and each representa halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, amercapto group or an alkylthio group; the ring B is a thiazole ring, anisothiazole ring or a pyrazole ring, and the ring B may have at leastone substituent selected from the group consisting of an alkyl group, ahaloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group andan acyl group; Z^(a) represents a hydroxyl group, an alkoxy group, amercapto group, an alkylthio group, an N-alkyl-substituted amino group(e.g., an N,N-dialkylamino group) or an N-acyl-substituted amino group(e.g., an N,N-diacylamino group); Z^(b) represents a hydrogen atom, analkyl group, a hydroxyl group or an alkoxy group; the ring C² representsa 5 to 8-membered ring (e.g., a 5 to 7-membered ring, and preferably a5- or 6-membered ring) having G¹ and G², and contains at least onehetero atom selected from the group consisting of a nitrogen atom (N),an oxygen atom (O) and a sulfur atom (S) as a constituent atom thereof;G¹ represents a nitrogen atom (N), CH or CH₂ depending on thearomaticity or nonaromaticity of the ring C²; G² represents a nitrogenatom (N), an oxygen atom (O) or NH; the ring C³ represents a 5 to8-membered ring (e.g., a 5 to 7-membered ring) having a nitrogen atomand optionally at least one hetero atom selected from the groupconsisting of an oxygen atom (O) and a sulfur atom (S) as constituentatom(s) thereof; L represents a linker selected from the groupconsisting of the formulae (1-a1) to (1-a6); Z², Z³ and q have the samemeanings as defined above.

The halogen atom, alkyl group, alkoxy group or alkylthio group, eachrepresented by and R², may include the same halogen atom (e.g., afluorine atom and a chlorine atom), C₁₋₆alkyl group (e.g., a C₁₋₄alkylgroup), C₁₋₆alkoxy group (e.g., a C₁₋₄alkoxy group) or C₁₋₆alkylthiogroup (e.g., a C₁₋₄alkylthio group) as the groups exemplified in thegroup R.

Concretely, the compounds represented by the formula (1) include, forexample, compounds shown in Tables 2 to 4.

TABLE 2 R¹ R² Ring B Linker L Ring C Representative compounds CompoundHalogen Alkyl 4-Alkyl Formula Formula[2-(4-halo-2-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid ofatom group thiazole- (1-a1) (5-a) 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethylester, etc. formula Halogen Alkoxy 2,5-diyl Formula[2-(4-halo-2-C₁₋₄alkoxyphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid(6-b) atom group (5-a), 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester,(5-b) or [2-(4-halo-2-C₁₋₄alkoxyphenyl-4-C₁₋₄alkylthiazol-5-yl]carbamicacid (5-d) 1-C₁₋₄alkyl-1H-indazol-5-ylmethyl ester,[2-(4-halo-2-C₁₋₄alkoxyphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid1-C₁₋₄alkyl-1H-benzotriazol-5-ylmethyl ester, etc. Alkyl Alkyl Formula[2-(2,4-diC₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid groupgroup (5-a) 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester, etc. AlkylAlkoxy Formula[2-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamicacid group group (5-a), 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester,(5-b) or[2-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamicacid (5-d) 1-C₁₋₄alkyl-1H-indazol-5-ylmethyl ester,[2-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamicacid 1-C₁₋₄alkyl-1H-benzotriazol-5-ylmethyl ester, etc. Alkoxy AlkoxyFormula [2-(2,4-diC₁₋₄alkoxyphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamicacid group group (5-a) 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester,etc. Halogen Alkoxy 2-Alkyl- Formula[5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamic acidatom group 2H- (5-a), 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester,pyrazole- (5-b) or[5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamic acid3,5-diyl (5-c) 1-C₁₋₄alky-1H-indazol-5-ylmethyl ester,[5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamic acid2-C₁₋₄alkyl-2H-indazol-6-ylmethyl ester, etc. Alkyl Alkyl Formula[5-(2,4-diC₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamic acidgroup group (5-a) 1-C₁₋₄alkyl-1H-benzimidazol-5-ylmethyl ester, AlkylAlkoxy[5-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamicacid group group (1-C₁₋₄alkyl-1H-benzimidazol-5-yl)methyl ester, etc.Halogen Alkyl 4-Alkyl Formula Formula(1-C₁₋₄alkyl-1H-benzimidazol-5-yl)carbamic acid atom group thiazole-(1-a4) (5-a) 2-(4-halo-2-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-ylmethylester, etc. 2,5-diyl

TABLE 3 R¹ R² Ring B Linker L Ring C Representative compounds CompoundAlkyl Alkoxy Isothiazole- Formula Formula(1-C₁₋₄alkyl-1H-benzimidazol-5-yl)carbamic acid of group group 3,5-diyl(1-a4) (5-a) 3-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)isothiazol-5-ylmethylester, formula Halogen Alkoxy (1-C₁₋₄alkyl-1H-benzimidazol-5-yl)carbamicacid (6-b) atom group 3-(4-halo-2-C₁₋₄alkoxyphenyl)isothiazol-5-ylmethylester, etc. Halogen Alkoxy 2-Alkyl- Formula(1-C₁₋₄alkyl-1H-benzimidazol-5-yl)carbamic acid atom group 2H- (5-a)5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethyl ester,pyrazole- or (2-C₁₋₄alkyl-2H-indazol-5-yl)carbarmic acid 3,5-diyl (5-c)5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethyl ester,etc. Alkyl Alkyl Formula (1-C₁₋₄alkyl-1H-benzimidazol-5-yl) carbamicacid group group (5-a)5-(2,4-diC₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethyl ester, AlkylAlkoxy (1-C₁₋₄alkyl-1H-benzimidazol-5-yl)carbamic acid group group5-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethylester, etc. Compound Halogen Alkyl 4-Alkyl Formula Formula[2-(4-halo-2-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid ofatom group thiazole- (1-a1) (5-j)3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethyl ester, etc. formulaHalogen Alkoxy 2,5-diyl Formula[2-(4-halo-2-C₁₋₄alkoxyphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid(6-c) atom group (5-h)2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-ylmethyl ester, or[2-(4-halo-2-C₁₋₄alkoxyphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid(5-j) 3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethyl ester, etc.Alkyl Alkyl Formula[2-(2,4-diC₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamic acid groupgroup (5-j) 3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethyl ester,etc. Alkyl Alkoxy Formula[2-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-yl]carbamicacid group group (5-j) 3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethylester, etc. Halogen Alkoxy 2-Alkyl- Formula[5-(4-halo-2-C₁₋₄alkoxyphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamic acidatom group 2H- (5-j) 3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethylester, Alkyl Alkoxy pyrazole-[5-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-yl]carbamicacid group group 3,5-diyl3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-ylmethyl ester, etc.

TABLE 4 R¹ R² Ring B Linker L Ring C Representative compounds CompoundHalogen Alkyl 4-Alkyl Formula Formula(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)carbamic acid of atom groupthiazole- (1-a4) (5-j)2-(4-halo-2-C₁₋₄alkylphenyl)-4-C₁₋₄alkylthiazol-5-ylmethyl ester, etc.formula 2,5-diyl (6-c) Halogen Alkoxy Isothiazole- Formula(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)carbamic acidatom group 3,5-diyl (5-i)3-(4-halo-2-C₁₋₄alkoxyphenyl)isothiazol-5-ylmethyl ester, or(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)carbamic acid (5-j)3-(4-halo-2-C₁₋₄alkoxyphenyl)isothiazol-5-ylmethyl ester, etc. HalogenAlkoxy 2-Alkyl- Formula(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)carbamic acid atomgroup 2H- (5-h),5-(4-halo-2-C1-4alkoxyphenyl)-2-C1-4alkyl-2H-pyrazol-3-ylmethyl ester,pyrazole- (5-i) or(1,2,3,4-tetrahydrabenzo[4,5]imidazo[1,2-a]pyridin-7-yl)carbamic acid3,5-diyl (5-j)5-(4-halo-2-C1-4alkoxyphenyl)-2-C1-4alkyl-2H-pyrazol-3-ylmethyl ester,(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)carbamic acid5-(4-halo-2-C1-4alkoxyphenyl)-2-C1-4alkyl-2H-pyrazol-3-ylmethyl ester,etc. Alkyl Alkyl Formula(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)carbamic acid groupgroup (5-h) 5-(2,4-diC₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethylester, Alkyl Alkoxy or(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)carbamic acid group group(5-j) 5-(2,4-diC₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethyl ester,(2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-6-yl)carbamic acid5-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethylester, (3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)carbamic acid5-(2-C₁₋₄alkoxy-4-C₁₋₄alkylphenyl)-2-C₁₋₄alkyl-2H-pyrazol-3-ylmethylester, etc.

The present invention also includes a salt (e.g., a salt with apharmacologically or physiologically acceptable acid or base) of thecompound represented by the formula (1). The acid for forming such asalt may include an inorganic acid (e.g., hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, and phosphoric acid) and an organicacid (e.g., an organic carboxylic acid such as acetic acid, propionicacid, trichloroacetic acid, trifluoroacetic acid, oxalic acid, succinicacid, fumaric acid, or maleic acid; an hydroxycarboxylic acid such aslactic acid, malic acid, tartaric acid, or citric acid; and a sulfonicacid such as methanesulfonic acid or toluenesulfonic acid). As the base,there may be mentioned, for example, an inorganic base (such as ammonia;an alkali metal hydroxide such as sodium hydroxide or potassiumhydroxide; an alkali metal carbonate; an alkaline earth metal hydroxidesuch as calcium hydroxide or magnesium hydroxide; and an alkaline earthmetal carbonate such as calcium carbonate) and an organic base [forexample, an aliphatic amine (e.g., an alkylamine such as triethylamine;an alkanolamine such as ethanolamine; and a polyamine such as analkylenediamine), an alicyclic amine (e.g., a dicycloalkylamine such asdicyclohexylamine), an aromatic amine (e.g., an N-alkyl-substitutedaniline such as N,N-dimethylaniline), and a heterocyclic amine (e.g., a5- or 6-membered ring such as pyrrolidine, pyridine, or morpholine)].These acids or bases may be used alone or in combination.

The compound or the salt thereof of the present invention may be ananhydride or a hydrate or may be a solvate (e.g., a solvate of anorganic solvent such as ethanol). Moreover, the compound or the saltthereof of the present invention also includes a hydrate or solvate ofthe compound of the formula (1) or the salt thereof, and in addition, anisolated crystal (e.g., a polymorphic crystalline substance). Moreover,the compound or the salt thereof according to the present invention alsoincludes a tautomer, optically active substance having an asymmetriccarbon atom (such as (R)-body, (S)-body, diastereomer), or racemic bodyof the compound of the formula (1) or the salt thereof, or a mixture ofthese compounds. Further, the end group or heterocyclic group, or othergroups of the compound or the salt thereof may be modified for forming apro-drug which expresses an activity in a living body (or an activemetabolite). The pro-drug may include, for example, a compound whichexpresses an activity by metabolism such as hydrolysis, oxidation,reduction, or transesterification (for example, an ester body, etherbody, alcohol body, or amide body of the compound of the formula (1)).The compound or the salt thereof of the present invention has a highsafety.

[Production Process]

The compound represented by the formula (1) or the salt thereof can beproduced by linking a unit represented by the group A, a unitrepresented by the ring B, a unit represented by the linker L, and aunit represented by the ring C, and the order to be linked is notparticularly limited to a specific one. For example, the compound or thesalt thereof can be produced according to the following reaction scheme(i):

wherein L¹ and L² represent groups which allow to react with each otherto form the linker L; the group A, the ring B, the ring C, L and n havethe same meanings as defined above.

In the reaction step (i), the groups represented by L¹ and L² are notparticularly limited to a specific one as far as these groups allow toreact with each other to form the linker L. The groups L¹ and L² aresuitably selected depending on the species of the linker L, and may forexample be functional groups which allow to react with each other toform a bond. Each one of the groups L¹ and L² may be the functionalgroup (end group) or a group having the functional group. The functionalgroup may include a haloalkyl group, a hydroxyl group, an aldehyde group(formyl group), a carboxyl group, a carbazoyl group, a hydroxamic acidgroup, an amino group, a hydrazino group, an aminocyano group, anisocyanate group, an isothiocyanato group, and other groups. In thegroup having the functional group, the residue that the functional groupis removed from the group having the functional group may include analkylene group.

More specifically, the compound represented by the formula (1) or thesalt thereof can be prepared according to the following reaction scheme(ii):

wherein the groups J and K are located at an end of the compound havingthe ring B and an end of the compound having the ring C, respectively,and allow to react with each other to link the compound having the ringB and the compound having the ring C; L^(1a) and L^(2a) are the same ordifferent and each represent an alkylene group; L³ represents a linkerrepresented by any one of the following formulae (1-a) to (1-i); j and kare the same or different and each are 0 or 1; and the group A, the ringB, the ring C and n have the same meanings as defined above.

In the reaction step (ii), the groups J and K are not particularlylimited to a specific one as far as these groups allow to react witheach other to link the compound having the ring B and the compoundhaving the ring C. These groups are suitably selected depending on thespecies of the basic skeleton L³ of the linker L[-(L^(1a))_(j)-L³-(L^(2a))_(k)-]. Concrete examples of the combinationof the groups J and K corresponding to the basic skeleton L³ of thelinker L are shown in Table 5.

TABLE 5 Basic skeleton L³ End group J End group K

  (1-a) Isocyanate group Hydroxyl group

  (1-b) Carboxyl group Hydrazino group

  (1-c) Carbazoyl group [—C(O)—NH—NH₂] Formyl group

  (1-d) Amino group Carboxyl group

  (1-r) Aminocyano group [—C═N—NH₂] Formyl group

  (1-f) Carboxyl group Hydroxyamino group —O— Hydroxyl group Haloalkylgroup (1-g) Haloalkyl group Hydroxyl group

  (1-h) Isothiocyanato group Hydroxyl group

  (1-i) Carboxyl group Carbazoyl group Carbazoyl group Carboxyl group

In Table 5, as the combination of the groups J and K, the combination inwhich the left end and the right end of the linker L are linked to thering B and the ring C, respectively, is shown. Use of the compound ofthe ring B having the group J and the compound of the ring C having thegroup K can easily produce the compound in which the left end and theright end of the linker L are linked to the ring C and the ring B,respectively.

The alkylene group (including an alkylidene group) represented by eachof L^(1a) and L^(2a) may include a straight chain or branched chainalkylene group (for example, a C₁₋₄alkylene group, and preferably aC₁₋₂alkylene group) such as methylene, 1,1-ethanediyl, ethylene(1,2-ethanediyl), 1,1-propanediyl, propylene (1,2-propanediyl),trimethylene, or tetramethylene group. The species of L^(1a) and L^(2a)may be the same or different from each other.

In the formation reaction of the linker, the ratio (the amount to beused) of the compound (7-a) [or the compound (7-c)] and the compound(7-b) [or the compound (7-d)] may be the ratio at which L¹ (end group J)and L² (end group K) are equivalent or almost equivalent. The ratio(molar ratio) of the compound (7-a) [or the compound (7-c)] relative tothe compound (7-b) [or the compound (7-d)] may for example be about 2/1to 1/2, preferably about 1.5/1 to 1/1.5, and more preferably about 1.2/1to 1/1.2 in a ratio of the former/the latter.

The formation reaction of the linker may be carried out in the presenceof a solvent. The solvent is not particularly limited to a specific oneas far as the solvent is inactive to the reaction. The solvent maysuitably be selected depending on the species of the raw materialcompounds (7-a) to (7-d), the species of the reaction, and others andmay include, for example, a hydrocarbon (e.g., an aliphatic hydrocarbonsuch as pentane or hexane; an alicyclic hydrocarbon such as cyclohexane;and an aromatic hydrocarbon such as benzene, toluene, or xylene), ahalogen-containing solvent (e.g., a halogenated hydrocarbon such asmethylene chloride, chloroform, carbon tetrachloride, bromoform, orethylene chloride), an alcohol (e.g., an alkanol such as methanol,ethanol, propanol, isopropanol, butanol, isobutanol, or t-butanol; and aglycol such as ethylene glycol or propylene glycol), an ether (e.g., achain ether such as ethyl ether or isopropyl ether; and a cyclic ethersuch as dioxane, tetrahydrofuran, or tetrahydropyran), a cellosolve(e.g., a C₁₋₄alkyl cellosolve such as methyl cellosolve or ethylcellosolve), a cellosolve acetate (e.g., a C₁₋₄alkyl cellosolve acetatesuch as ethyl cellosolve acetate), a carbitol (e.g., methyl carbitol), aketone (e.g., a dialkyl ketone such as acetone, methyl ethyl ketone,diisopropyl ketone, or isobutyl methyl ketone), an organic carboxylicacid (e.g., acetic acid), an ester (e.g., an acetic acid ester such asmethyl acetate, ethyl acetate, butyl acetate), an amide (e.g.,formamide; an N-mono- or di-C₁₋₄alkylformamide such as N-methylformamideor N,N-dimethylformamide; and an N-mono- or di-C₁₋₄alkylacetamide suchas N-methylacetamide or N,N-dimethylacetamide), a pyridine (e.g.,pyridine and pyridine borane), and a nitrile (e.g., acetonitrile andbenzonitrile). These solvents may be used alone or as a mixed solvent.

Moreover, the formation reaction of the linker may be carried out in thepresence of a catalyst. The catalyst may include, for example, an acidcatalyst [for example, an inorganic acid (e.g., sulfuric acid), anorganic acid (e.g., p-toluenesulfonic acid), and Lewis acid], a basecatalyst {for example, an inorganic base [e.g., a metal hydroxide (e.g.,an alkali metal or alkaline earth metal hydroxide such as sodiumhydroxide) and a metal carbonate (e.g., an alkali metal or alkalineearth metal carbonate such as sodium carbonate)], an organic base [forexample, an aliphatic amine [for example, a primary to tertiaryaliphatic amine, e.g., an aliphatic tertiary amine such as atriC₁₋₄alkylamine (such as triethylamine, diethylmethylamine,diisopropylethylamine, tri-n-propylamine, or tributylamine)], anaromatic amine (for example, a primary to tertiary aromatic amine, e.g.,an aromatic tertiary amine such as N,N-dimethylaniline), and aheterocyclic amine (for example, a primary to tertiary heterocyclicamine, e.g., a heterocyclic tertiary amine such as picoline, pyridine,pyrazine, pyrimidine, pyridazine, 1-methylimidazole, triethylenediamine,N,N-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]unde-7-cene)]}.These catalysts may be used alone or in combination.

The amount of the catalyst may for example be about 0.0001 to 5 mol andpreferably about 0.001 to 1 mol relative to 1 mol of the compound (7-a)[or the compound (7-c)] or the compound (7-b) [or the compound (7-d)].

The formation reaction of the linker may be conducted under a roomtemperature or a heated condition. Moreover, the reaction can beconducted in air or under an inactive (or inert) gas atmosphere (such asnitrogen, helium, or argon gas). The reaction may be carried out underan atmospheric pressure or an applied pressure. The reaction time is notparticularly limited to a specific one and may for example be about 0.1to 60 hours and preferably about 0.5 to 50 hours.

After the completion of the reaction, the compound represented by theformula (1) [or the formula (7-e)] or the salt thereof may be separatedor purified from the reaction mixture by a conventional separation orpurification (or isolation) method, for example, filtration,distillation, condensation, precipitation, crystallization,recrystallization, decantation, extraction, drying, washing,chromatography, and a combination thereof.

(Compound Represented by the Formula (7-a))

The compound represented by the formula (7-a) can be prepared accordingto a conventional method, for example, any one of the following reactionschemes (iii) to (v).

wherein A¹ represents the group A or a residue of the group A; thegroups A² and A³ are located at an end of the compound having the groupA¹ and an end of the compound having the ring B, respectively, and allowto react with each other to link the group A and the ring B; B¹ and B²are groups which allow to react with each other to form the ring B, B³and B⁴ are groups which allow to react with each other to form the ringB; the group A, the ring B, the group L¹ and n have the same meanings asdefined above.

In the reaction step (iii), the method for linking the group A to thering B is not particularly limited to a specific one, and conventionaladdition reaction, substitution reaction, coupling reaction (forexample, a cross-coupling reaction such as Suzuki coupling reaction), orother reactions can be used. As the combination of A² and A³, forexample, when A² is a boronic acid group [—B(OH)₂] and A³ is a halogenatom, both groups allow to react with each other to link A¹ (=A) to thering B, and the compound represented by the formula (7-a) is obtained.

The compound represented by the formula (8-a) may include a compound inwhich A² is a boronic acid group, for example, an arylboronic acid[e.g.,a halo-alkoxyarylboronic acid (preferably ahalo-C₁₋₆alkoxyC₆₋₁₀arylboronic acid) such as4-chloro-2-methoxyphenylboronic acid].

The compound represented by the formula (8-b) may include a compound inwhich A³ is a halogen atom and L¹ is an alkoxycarbonyl group [e.g., analkyl 4-halo-1-alkyl-1H-pyrrole-2-carboxylate (preferably a C₁₋₄alkyl4-halo-1-C₁₋₄alkyl-1H-pyrrole-2-carboxylate) such as ethyl4-bromo-1-methyl-1H-pyrrole-2-carboxylate], and others.

The ratio (amount to be used) of the compound represented by the formula(8-a) relative to the compound represented by the formula (8-b) may forexample be about 99/1 to 1/99, preferably about 90/10 to 10/90, and morepreferably about 85/15 to 15/85 in a molar ratio of the former/thelatter.

The reaction of the compound (8-a) and the compound (8-b) may be carriedout in the presence of an inorganic base. As the inorganic base, theremay be mentioned a metal carbonate (for example, an alkali metalcarbonate such as potassium carbonate or sodium carbonate), and others.These inorganic bases may be used alone or in combination. The ratio(the amount to be used) of the inorganic base may for example be about0.1 to 10 mol and preferably about 0.5 to 5 mol relative to 1 mol of thetotal of the compound (8-a) and the compound (8-b).

The reaction of the compound (8-a) and the compound (8-b) may be carriedout in the presence of a catalyst [for example, a palladium-seriescatalyst such as tetrakis(triphenyphosphine)palladium]. The ratio (theamount to be used) of the catalyst may be not more than 0.1 mol andpreferably not more than 0.01 mol (e.g., about 0.001 to 0.01 mol)relative to 1 mol of the total of the compound represented by theformula (8-a) and the compound represented by the formula (8-b).

The reaction of the compound (8-a) and the compound (8-b) may be carriedout in the presence of a solvent. The solvent is not particularlylimited to a specific one as far as the solvent is inactive to thereaction. The solvent may include water, a hydrocarbon (e.g., analiphatic hydrocarbon such as pentane or hexane; an alicyclichydrocarbon such as cyclohexane; and an aromatic hydrocarbon such asbenzene, toluene, or xylene), an amide (e.g., formamide; an N-mono- ordi-C₁₋₄alkylformamide such as N-methylformamide orN,N-dimethylformamide; and an N-mono- or di-C₁₋₄alkylacetamide such asN-methylacetamide or N,N-dimethylacetamide), and others. These solventsmay be used alone or as a mixed solvent. Among these solvents, mixedsolvent of a water and an amide [for example, a mixed solvent containingwater and an amide in a ratio (volume ratio) of 10/90 to 50/50 as theformer/the latter] is widely used.

The reaction of the compound (8-a) and the compound (8-b) can beconducted under a room temperature or a heated condition. For example,the reaction can be conducted at a temperature of about 10 to 150° C.(preferably about 20 to 100° C.). Moreover, the reaction can beconducted in air or under an inactive (or inert) gas atmosphere (such asnitrogen, helium, or argon gas). The reaction may be carried out underan atmospheric pressure or an applied pressure. The reaction time is notparticularly limited to a specific one and may for example be about 0.1to 20 hours, preferably about 0.5 to 15 hours, and more preferably about1 to 10 hours.

In the reaction step (iv), the method for forming the ring B is notparticularly limited to a specific one and a known method for producinga heterocyclic ring [for example, a method described in the fourthedition Jikken Kagaku Koza (Experimental Chemistry Lecture) 24, OrganicChemistry VI, Hetero element/representative metal element compounds,edited by The Chemical Society of Japan, published by Maruzen Company,Limited, p. 463 to 549] can be used. For example, a reaction such as areaction of a thioamide (or an amide, a ketone) and an α-halo ketone(e.g., Hantzsch method, Feist-Benary method), a reaction of athiosemicarbazide (or a semicarbazide) and an acid halide, or a reactionof a hydroxyiminoacetonitrile and an alkyl thioglycolate can be used forcyclization. In the cyclization reaction, representative combinationexamples of the compound (8-c) and the compound (8-d) as well asrepresentative examples of the compound (7-a) are shown in Table 6.

TABLE 6 Compound (8-c) Compound (8-d) Compound (7-a)

In the formulae of Table 6, Halo represents a halogen atom (such as achlorine atom or a bromine atom); the group A, the group L¹ and n havethe same meanings as defined above.

In the reaction step (v), the method for forming the ring B is notparticularly limited to a specific one and a known method for producinga heterocyclic ring [for example, a method described in the fourthedition Jikken Kagaku Koza (Experimental Chemistry Lecture) 24, OrganicChemistry VI, Hetero element/representative metal element compounds,edited by The Chemical Society of Japan, published by Maruzen Company,Limited, p. 463 to 549] can be used. For example, a cyclization reactionof an α,β-unsaturated ketone (or a 1,2-diketone) and a hydrazine (or ahydroxylamine, an amide) can be used. In the cyclization reaction,representative combination examples of the compound (8-e) and thecompound (8-f) as well as representative examples of the compound (7-a)are shown in Table 7.

TABLE 7 Compound (8-e) Compound (8-f) Compound (7-a)

H₂N—NH₂

NH₂OH

In the formulae of Table 7, the group A, the group L¹ and n have thesame meanings as defined above.

In the reaction steps (iv) and (v), each of the ratio (the amount to beused) of the compound (8-c) relative to the compound (8-d) and the ratio(the amount to be used) of the compound (8-e) relative to the compound(8-f) may be about 90/10 to 10/90, preferably about 80/20 to 20/80, andmore preferably about 70/30 to 30/70 in a molar ratio of the former/thelatter.

The reaction steps (iv) and (v) may be carried out in the presence of asolvent. The solvent is not particularly limited to a specific one asfar as the solvent is inactive to the reaction. The solvent may include,for example, a hydrocarbon (e.g., an aliphatic hydrocarbon such aspentane or hexane; an alicyclic hydrocarbon such as cyclohexane; and anaromatic hydrocarbon such as benzene, toluene, or xylene) and an alcohol(e.g., an alkanol such as methanol or ethanol). These solvents may beused alone or as a mixed solvent. Among these solvents, a C₁₋₄alkanolsuch as ethanol is widely used.

The reaction steps (iv) and (v) can be carried out under a roomtemperature or a heated condition. For example, the reaction can beconducted at a temperature of about 10 to 150° C. (preferably about 20to 100° C.). Moreover, the reaction can be conducted in air or under aninactive (or inert) gas atmosphere (such as nitrogen, helium, or argongas). The reaction may be carried out under an atmospheric pressure oran applied pressure. The reaction time is not particularly limited to aspecific one and may for example be about 1 to 50 hours, preferablyabout 5 to 40 hours, and more preferably about 10 to 30 hours.

(Compound Represented by the Formula (7-b))

The compound represented by the formula (7-b) may for example be any oneof the following formulae (7-b1) to (7-b3):

wherein the group L², the group Z¹, the group Z², the group Z³, the ringC¹, the ring C², the ring C³, G¹ to G⁴, p and q have the same meaningsas defined above.

The compound represented by the formula (7-b1) may be synthesized by aconventional method or may be a product on the market. Specifically, thecompound represented by the formula (7-b1) may include a compoundcorresponding to the ring represented by the formula (4-a), for example,a compound in which the end group of L² (the group K) is a hydroxylgroup [e.g., an aralkyl alcohol (preferably a C₆₋₁₀arylC₁₋₄alkylalcohol) such as benzyl alcohol; a haloaralkyl alcohol (preferably ahaloC₆₋₁₀arylC₁₋₄alkyl alcohol) such as 4-fluorobenzyl alcohol; analkoxy-aralkyl alcohol (preferably a C₁₋₄alkoxy-C₆₋₁₀arylC₁₋₄alkylalcohol) such as 4-methoxybenzyl alcohol or 4-methoxyphenethylalcohol;an alkylthio-aralkyl alcohol (preferably aC₁₋₄alkylthio-C₆₋₁₀arylC₁₋₄alkyl alcohol) such as 4-methylthiobenzylalcohol; an N,N-dialkyl-aralkyl alcohol (preferably anN,N-diC₁₋₄alkyl-C₆₋₁₀arylC₁₋₄alkyl alcohol) such as 3- or4-(N,N-dimethyl)-benzyl alcohol; and a halo-alkoxy-aralkyl alcohol(preferably a halo-C₁₋₄alkoxy-C₆₋₁₀arylC₁₋₄alkyl alcohol) such as3-fluoro-4-methoxybenzyl alcohol], and compounds each of whichcorresponds to each of these compounds and in each of which the endgroup of L² (the group K) is a formyl group, a carboxyl group, acarbazoyl group or other groups.

The compound represented by the formula (7-b2) or (7-b3) may be aproduct on the market or may be synthesized by a known process forproducing a heterocyclic ring (for example, a method described in thefourth edition Jikken Kagaku Koza (Experimental Chemistry Lecture) 24,Organic Chemistry VI, Hetero element/representative metal elementcompounds, edited by The Chemical Society of Japan, published by MaruzenCompany, Limited, p. 463 to 549; a method described in J. Chem. Soc.,1963, 4666-4669; and a method described in J. Chem. Soc. Perkin I, 1979,1056-1062). For example, the compound represented by the formula (7-b2)or (7-b3) can be prepared according to the following reaction scheme(vi) or (vii):

wherein C^(2a) represents a component for forming the ring C²; and thegroup L², the ring C², the ring C³, and G¹ to G⁴ have the same meaningsas defined above.

In the formulae (9-a) and (9-b), the broken line indicates that each ofG¹ to G³ may bind to a hydrogen atom depending on the species of G¹ toG³.

The compound (9-b) is not particularly limited to a specific one as faras the compound is a component for forming the ring C². As the compound(9-b), at least an acid component (an organic acid) is usually employed.The acid component may include an alkanoic acid (e.g., a C₁₋₆alkanoicacid) such as formic acid, acetic acid, or propionic acid, or an acidanhydride thereof. In the case where a nitrogen atom is introduced intothe ring C², nitrous acid or a salt (an alkali metal salt such as asodium salt) thereof or an ester thereof (e.g., a C₁₋₆alkyl ester ofnitrous acid, such as isoamyl nitrite) is widely used in addition to theacid component.

Representative examples of the combination of the compound (9-a) and thecompound (9-b) are shown in Table 8.

TABLE 8 Compound (9-a) Compound (9-b) Compound (7-b2)

NaNO₂

In the formulae of Table 8, the group L² and the group Z have the samemeanings as defined above.

In the cyclization reaction (vi), the ratio (the amount to be used) ofthe compound (9-a) relative to the compound (9-b) may be about 2/1 to1/2 and preferably about 1.5/1 to 1/1.5 in a molar ratio of theformer/the latter. Since the organic acid such as formic acid also actas a reaction solvent, the molar quantity of the compound (9-b) may bein excess of that of the compound (9-a) [for example, the ratio of thecompound (9-a) relative to the compound (9-b) may be about 1/2 to 1/50in a molar ratio of the compound (9-a)/the compound (9-b)].

In the cyclization reaction (vii), the intramolecular cyclization of thecompound (9-c) in the presence of a peroxide (such as hydrogen peroxidesolution) and an organic acid (such as formic acid) forms a 5-memberedring adjacent to both the benzene ring and the ring C³. The organic acidsuch as formic acid acts as a reactant and a reaction solvent; the molarquantity of the organic acid is usually in excess of that of thecompound (9-c) [for example, the ratio of the compound (9-c) relative tothe organic acid may be about 1/2 to 1/50 in a molar ratio of thecompound (9-c)/the organic acid].

The cyclization reactions (vi) and (vii) may be carried out in thepresence of a solvent. The solvent may include a hydrocarbon (e.g., analiphatic hydrocarbon such as pentane or hexane; an alicyclichydrocarbon such as cyclohexane; and an aromatic hydrocarbon such asbenzene, toluene, or xylene), a halogen-containing solvent (e.g., ahalogenated hydrocarbon such as methylene chloride, chloroform, carbontetrachloride, bromoform, or ethylene chloride), and an ether (e.g., achain ether such as ethyl ether or isopropyl ether; and a cyclic ethersuch as dioxane, tetrahydrofuran, or tetrahydropyran). These solventsmay be used alone or as a mixed solvent.

The cyclization reactions (vi) and (vii) can be carried out under a roomtemperature or a heated condition. For example, the reaction can beconducted at a temperature of about 10 to 150° C. (preferably about 20to 100° C.). Moreover, the reaction can be conducted in air or under aninactive (or inert) gas atmosphere (such as nitrogen, helium, or argongas). The reaction may be carried out under an atmospheric pressure oran applied pressure. The reaction time is not particularly limited to aspecific one and may for example be about 1 minute to 50 hours,preferably about 5 minutes to 40 hours, and more preferably about 10minutes to 30 hours.

In the compound (7-a) [or the compound (7-c)] or the compound (7-b) [orthe compound (7-d)], L¹ (the end group J) or L² (the end group K) may begroups which allow to directly react with each other to form a linker,or may be precursor groups of the groups which can form a linker. Theprecursor groups can be converted into an objective group by using aknown reaction (such as an oxidation reaction, a reduction reaction, anaddition reaction, a condensation reaction, a hydrolysis reaction, or arearrangement reaction). For example, an alkoxycarbonyl group can beconverted into a carboxyl group by a hydrolysis reaction; a carboxylgroup can be (a) converted into an acid azide group by a reaction with adiarylphosphoryl azide, and the acid azide group can be converted intoan isocyanate group by Curtius rearrangement reaction, (b) convertedinto a carbazoyl group by a reaction with hydrazine, (c) converted intoa carbamoyl group by a reaction with ammonia, and the carbamoyl groupcan be converted into an isothiocyanato group by a reaction with thionylchloride, or (d) converted into an aldehyde group by a reductionreaction, and the aldehyde group can be (d1) converted into an alkylgroup by Clemmensen reduction, and the alkyl group can be converted intoa haloalkyl group by halogenation or (d2) converted into an aminocyanogroup by a reaction with hydrazine.

The reaction for converting L¹ (the end group J) or L² (the end group K)into an objective group and the formation reaction of the linker L maybe conducted in respective reaction systems or in the same reactionsystem.

Specifically, one example of the method for producing the linkerrepresented by the formula (1-a) (a method using Curtius rearrangement)is explained in detail as follows. In this method, a compoundrepresented by the formula (7-h) is obtained by a reaction of acarboxylic acid represented by the formula (7-f), an alcohol representedby the formula (7-g) and a diarylphosphoryl azide (adiC₆₋₁₀arylphosphoryl azide such as diphenylphosphoryl azide) in thepresence of a base, according to the following reaction scheme:

wherein the group A, the ring B, the ring C, the group L^(1a), the groupL^(2a), j, k and n have the same meanings as defined above. Morespecifically, a compound represented by the formula (7-h) is obtainedaccording to the following reaction scheme:

wherein the group A, the ring B, the ring C, the group L^(1a), the groupL^(2a), j, k and n have the same meanings as defined above.

That is, the compound represented by the formula (7-h) is obtained by astep for allowing the carboxylic acid represented by the formula (7-f)to react with the diarylphosphoryl azide in the presence of the base toproduce a carboxylic acid azide, a step for converting an acid azidegroup of the carboxylic acid azide into an isocyanate group by Curtiusrearrangement to produce an isocyanate represented by the formula (7-j),and a step for allowing the isocyanate to react with the alcoholrepresented by the formula (7-g).

The ratio (the amount to be used) of the carboxylic acid represented bythe formula (7-f) relative to the alcohol represented by the formula(7-g) is not particularly limited to a specific one, and may be theratio at which the carboxyl group and the hydroxyl group may beequivalent or almost equivalent. For example, the ratio of thecarboxylic acid relative to the alcohol may be about 2/1 to 1/2,preferably about 1.5/1 to 1/1.5, and more preferably about 1.2/1 to1/1.2 in a molar ratio of the former/the latter.

The ratio (the amount to be used) of the diarylphosphoryl azide may forexample be about 0.1 to 2 mol, preferably about 0.5 to 1.5 mol, and morepreferably 0.8 to 1.2 mol relative to 1 mol of the carboxylic acidrepresented by the formula (7-f).

The base may be a basic inorganic compound and is usually a basicorganic compound. As the basic organic compound, a tertiary amine iswidely used. For example, the basic organic compound may include analiphatic amine (e.g., a triC₁₋₆alkylamine such as trimethylamine ortriethylamine; and an N,N,N′,N′-tetraC₁₋₄alkylC₁₋₄alkanediamine such asN,N,N′,N′-tetramethylethylenediamine orN,N,N′,N′-tetramethylpropanediamine), an alicyclic amine (e.g., atriC₅₋₆cycloalkylamine such as tricyclohexylamine; adiC₅₋₆cycloalkylC₁₋₄alkylamine such as dicyclohexylethylamine; and adiC₁₋₄alkylC₅₋₆cycloalkylamine such as diethylcyclohexylamine), and anaromatic amine (e.g., an N,N-diC₁₋₄alkylaniline such asN,N-dimethylaniline or N,N-diethylaniline; and an N-arylpyrrolidine suchas N-phenylpyrrolidine). These bases may be used alone or incombination. Among these bases, a triC₁₋₄alkylamine such astriethylamine is widely used.

The ratio (the amount to be used) of the base is, for example, about0.01 to 1 mol and preferably about 0.1 to 0.5 mol relative to 1 mol ofthe total of the carboxylic acid represented by the formula (7-f), thealcohol represented by the formula (7-g) and the diarylphosphoryl azide.

The reaction of the compound (7-f) and the compound (7-g) may be carriedout in the presence of a solvent. The is not particularly limited to aspecific one as far as the solvent is inactive to the reaction. Thesolvent may include a hydrocarbon (e.g., an aliphatic hydrocarbon suchas pentane or hexane; an alicyclic hydrocarbon such as cyclohexane; andan aromatic hydrocarbon such as benzene, toluene, or xylene), ahalogen-containing solvent (e.g., a halogenated hydrocarbon such asmethylene chloride, chloroform, carbon tetrachloride, bromoform, orethylene chloride), an ether (e.g., a chain ether such as ethyl ether orisopropyl ether; and a cyclic ether such as dioxane, tetrahydrofuran, ortetrahydropyran), a ketone (e.g., a dialkyl ketone such as acetone,methyl ethyl ketone, diisopropyl ketone, or isobutyl methyl ketone), anester (e.g., an ester of acetic acid, such as methyl acetate, ethylacetate, or butyl acetate), and a nitrile (e.g., acetonitrile). Thesesolvents may be used alone or as a mixed solvent. Among these solvents,an aromatic hydrocarbon such as toluene is widely used.

The reaction of the compound (7-f) and the compound (7-g) can beconducted under a room temperature or a heated condition. For example,the reaction can be conducted at a temperature of about 10 to 150° C.(preferably about 20 to 100° C.). Moreover, the reaction can beconducted in air or under an inactive (or inert) gas atmosphere (such asnitrogen, helium, or argon gas). The reaction may be carried out underan atmospheric pressure or an applied pressure. The reaction time is notparticularly limited to a specific one and may for example be about 0.1to 20 hours, preferably about 0.5 to 15 hours, and more preferably about1 to 10 hours.

After the completion of the reaction, the compound represented by theformula (7-h) or the salt thereof may be separated or purified from thereaction mixture by a conventional separation or purification (orisolation) method, for example, filtration, distillation, condensation,precipitation, crystallization, recrystallization, decantation,extraction, drying, washing, chromatography, and a combination thereof.

[Use and Pharmaceutical Composition]

The compound or the salt thereof of the present invention specificallybinds to the component protein Skp2 of ubiquitin ligase and is thususeful as a p27^(Kip1) ubiquitination inhibitor. Since the compound orthe salt thereof can inhibit the ubiquitination of p27^(Kip1) at a highactivity, for example, by inhibition of the dissociation of p27^(Kip1)from SCF^(Skp2) complex, resulting in effectively inhibiting thedegradation of p27^(Kip1) by proteasome, the compound or the saltthereof is also useful as a p27^(Kip1) degradation inhibitor. Moreover,since the compound or the salt thereof of the present invention recoversthe expression amount of p27^(Kip1) by inhibiting the degradation ofp27^(Kip1) and effectively induces cell death (apoptosis), the compoundor the salt thereof is also useful as a cell-death inducer and is usefulas a preventing and/or treating agent for a cell proliferative disease,for example, cancer, rheumatism, diabetes, adiposis, endometriosis,prostatomegaly, and inflammation. The compound or the salt thereof ofthe present invention is useful as a preventing and/or treating agentfor various cancers [for example, a solid cancer (e.g., an encephaloma,a cancer of the mouth, a cancer of the pharynx, a cancer of the larynx,a lung cancer, a digestive cancer (e.g., a cancer of the esophagus, acancer of the stomach, a cancer of the large intestine, a cancer of theliver, and a cancer of the pancreas), a urinary cancer (e.g., a cancerof the kidney, a cancer of the bladder, and a cancer of the prostate), acancer of the breast, a cancer of the uterus (or the uterine cervix), acancer of the ovary, a skin cancer, a cancer of the thyroid, and anosteosarcoma), and a blood cancer (e.g., a leukemia and a malignantlymphoma)]. In particular, the compound or the salt thereof of thepresent invention is useful as a preventing and/or treating agent for ahighly malignant (or intractable) cancer, for example, an encephaloma,an oral squamous cell cancer, a lung cancer, a cancer of the stomach, acancer of the large intestine, a cancer of the liver, a cancer of thebladder, a cancer of the prostate (e.g., a hormone refractory prostatecancer), a cancer of the breast, a cancer of the uterus (or the uterinecervix), a cancer of the ovary, and a blood cancer. The preventingand/or treating agent for the cancer is preferably used due toprevention of the development and proliferation (e.g., progression,recurrence, and metastasis) of the cancer.

The above-mentioned compound may be used as a medicine alone, or theabove-mentioned crystal may be used in combination with a carrier (e.g.,a pharmacologically or physiologically acceptable carrier) to provide apharmaceutical composition (or preparation). With respect to thepharmaceutical composition of the present invention, the carrier may besuitably selected depending on the form of the composition orpreparation (that is, the dosage form), the route of administration, theapplication (or use), and others. The dosage form is not particularlylimited to a specific one and may be a solid preparation (for example,powdered preparations, powders, granulated preparations (e.g., granulesand microfine granules or the like), spherical or spheroidalpreparations, pills, tablets, capsules (including soft capsules and hardcapsules), dry syrups, and suppositories), a semisolid preparation (forexample, creams, ointments, gels, gumdrop-like preparations, andfilm-like preparations, sheet-like preparations), a liquid preparation(for example, solutions, suspensions, emulsions, syrup, elixir, lotions,injectable solutions (or injections), and drops), and others. Moreover,sprays or aerosols of the powdered preparations and/or the liquidpreparation may be also included. Incidentally, the capsules may be acapsule filled with a liquid or a capsule filled with a solidpreparation (such as granules). Moreover, the preparation may be alyophilized preparation. Further, the preparation of the presentinvention may be a preparation releasing the active ingredient(s) at acontrolled rate (a sustained release preparation or a rapid-releasepreparation). The preparation may be a preparation for oraladministration or a preparation for parenteral administration (forexample, a nosal preparation (or a collunarium), an inhalantpreparation, and a preparation for transdermal administration).Furthermore, the preparation may be a preparation for topicaladministration (for example, solutions such as injectable solutions(e.g., aqueous injectable solutions and nonaqueous injectablesolutions), suspensions, ointments, plasters and pressure sensitiveadhesives, and cataplasms). The preparation of the present invention ispractically a solid preparation (particularly, a preparation for oraladministration) or a liquid preparation (a preparation for parenteraladministration, such as injectable solutions). The amount of thecompound or the salt thereof in the preparation of the present inventionis not particularly limited to a specific one. Depending on the dosageform, the amount of the compound or the salt thereof can for example beselected from the range of about 0.0001 to 99% by weight, and is usuallyabout 0.005 to 60% by weight (e.g., about 0.01 to 50% by weight) for asolid preparation or a semisolid preparation and is about 0.001 to 30%by weight (e.g., about 0.005 to 20% by weight) for a liquid preparation.

The carrier may for example be selected depending on the administrationroute and the application of preparation, from components (e.g., anexcipient, a binder, a disintegrant, a lubricant, and a coating agent)listed in Japanese Pharmacopoeia, (1) Handbook of PharmaceuticalExcipients (Maruzen Company, ltd., (1989)), (2) Japanese PharmaceuticalExcipients Dictionary 2000 (Yakuji Nippo Ltd., issued March, 2002), (3)Japanese Pharmaceutical Excipients Dictionary 2005 (Yakuji Nippo Ltd.,issued May, 2005), (4) Pharmaceutics, revised fifth edition (Nankodo,Co., Ltd. (1997)), and (5) Japanese Pharmaceutical Excipients 2003(Yakuji Nippo Ltd., issued August, 2003). For example, the carrier for asolid preparation is practically at least one member selected from thegroup consisting of an excipient, a binder, and a disintegrant.Moreover, the pharmaceutical composition may contain a lipid.

The excipient may include a saccharide or a sugar alcohol such aslactose, white sugar or refined sugar, glucose, sucrose, mannitol,sorbitol, or xylitol; a starch such as acorn starch; a polysaccharidesuch as a crystalline cellulose (including a microcrystallinecellulose); silicon dioxide or a silicate such as a light silicicanhydride or a synthetic aluminum silicate; and others. The binder mayinclude a water-soluble starch such as a pregelatinized starch or apartially pregelatinized starch; a polysaccharide such as agar, gumacacia (or gum arabic), dextrin, sodium alginate, a tragacanth gum, axanthan gum, a hyaluronic acid, or a sodium chondroitin sulfate; asynthetic polymer such as a polyvinylpyrrolidone, a polyvinyl alcohol, acarboxyvinyl polymer, a polyacrylic polymer, a polylactic acid, or apolyethylene glycol; a cellulose ether such as a methyl cellulose (MC),an ethyl cellulose (EC), a carboxymethyl cellulose (CMC), acarboxymethyl cellulose sodium, a hydroxyethyl cellulose (HEC), ahydroxypropyl cellulose (HPC), or a hydroxypropylmethyl cellulose(HPMC); and others. The disintegrant may include calcium carbonate, asodium carboxymethyl starch, a carboxymethyl cellulose or a salt thereof(e.g., a carmellose, a carmellose sodium, a carmellose calcium, and acroscarmellose sodium), a crosslinked polyvinylpyrrolidone(crospovidone), a low-substituted hydroxypropyl cellulose, and others.These carriers may be used alone or in combination.

For example, there may be used, as the coating agent, a saccharide or asugar, a cellulose derivative such as an ethyl cellulose or ahydroxymethyl cellulose, a poly(oxyethylene glycol), a cellulose acetatephthalate, a hydroxypropylmethyl cellulose phthalate, a methylmethacrylate-(meth)acrylic acid copolymer, and eudragit (a copolymer ofmethacrylic acid and acrylic acid). The coating agent may be an entericcomponent (e.g., a cellulose phthalate, a hydroxypropylmethyl cellulosephthalate, and a methyl methacrylate-(meth)acrylic acid copolymer) or agastric soluble component comprising a polymer containing a basiccomponent such as a dialkylaminoalkyl(meth)acrylate (e.g., eudragit).Moreover, the preparation may be a capsule having such an entericcomponent or gastric soluble component as a capsule shell.

In the carrier of the liquid preparation, an oil-based carrier mayinclude an oil derived from plants or animals (e.g., an oil derived fromvegetables such as a jojoba oil, an olive oil, a palm oil, or a cottonseed oil; and an oil derived from animals such as squalene), a mineraloil (e.g., a liquid petrolatum and a silicone oil), and others. Anaqueous carrier may include water (e.g., a purified water or a sterilewater, a distilled water for injection), a physiological saline, aRinger's solution, a glucose solution, a water-soluble organic solvent[for example, a lower aliphatic alcohol such as ethanol or isopropanol;a (poly)alkylene glycol (e.g., ethylene glycol and a polyethyleneglycol); and glycerin], dimethyl isosorbide, dimethylacetamide, andothers. Moreover, the carrier of the semisolid preparation may beselected from the carrier of the solid preparation and/or that of theliquid preparation. Further, the carrier of the semisolid preparationmay contain a lipid.

The lipid may include a wax (e.g., a bees wax, a carnauba wax, alanolin, a paraffin, and a petrolatum), a higher (or long chain) fattyacid ester [e.g., an alkyl ester of a saturated or unsaturated fattyacid, and an ester of a fatty acid with a polyvalent alcohol (such as apolyC₂₋₄alkylene glycol, glycerin, or a polyglycerin) (e.g., aglyceride)], a hardened (or hydrogenated) oil, a higher alcohol (e.g., asaturated aliphatic alcohol such as stearyl alcohol and an unsaturatedaliphatic alcohol such as oleyl alcohol), a higher fatty acid (e.g.,linoleic acid, linoleic acid, stearic acid and oleic acid), a metallicsoap (e.g., a metal salt of a fatty acid, such as a sodium salt of palmoil fatty acid or calcium stearate), and others.

In the preparation, known additives can be suitably used depending on anadministration route, a dosage form, and others. Such an additive mayinclude, for example, a lubricant (e.g., a talc, magnesium stearate, anda polyethylene glycol 6000), a disintegrant aid, an antioxidation agentor an antioxidant, an emulsifier (e.g., a variety of surfactants such asa nonionic surfactant), a dispersing agent, a suspending agent, adissolving agent, a dissolution aid, a thickener (e.g., a water-solublepolymer such as a carboxyvinyl polymer, a polyvinyl alcohol, acarrageen, or a gelatin; and a cellulose ether such as a carboxymethylcellulose), a pH adjusting agent or a buffer (e.g., a citric acid-sodiumcitrate buffer), a stabilizer, an antiseptic agent or a preservative(e.g., a paraben such as methyl paraben or butyl paraben), a fungicideor antibacterial agent (e.g., a benzoic acid compound such as sodiumbenzoate), an antistatic agent, a corrigent or a masking agent (e.g.,sweetening agent), a coloring agent (e.g., a dye and a pigment such ascolcothar), a deodorant or a perfume (e.g., an aromatic substance), analgefacient, an antifoaming agent, an isotonizing agent, and a soothingagent. These additives may be used singly or in combination.

In the injectable solution, usually, the dissolving agent, thedissolution aid, the suspending agent, the buffer, the stabilizer, thepreservative, and others may be used as the additive in practical cases.Incidentally, to powders for an injection (lyophilized preparations),which are dissolved or suspended in water (a water for injection) or atransfusion agent (such as a physiological saline, a glucose solution,or a Ringer's solution) before administration, may be added conventionaladditive (s) used for powders for an injection.

Moreover, in a topically administering preparation such as an inhalantpreparation or a transdermal absorption preparation, as the additive,usually, the dissolution aid, the stabilizer, the buffer, the suspendingagent, the emulsifier, the preservative, and others may be practicallyused.

The pharmaceutical composition of the present invention may be preparedby using a carrier component in addition to an effective ingredient, andif necessary, an additive and the like, with a conventional preparationmanner (for example, a production process described in JapanesePharmacopoeia 15^(th) edition or a process in accordance with theproduction process).

The compound or the salt thereof (including the p27^(Kip1)ubiquitination inhibitor, the p27^(Kip1) degradation inhibitor, thepreventing and/or treating agent for a cell proliferative disease, andthe pharmaceutical composition) of the present invention is safelyadministered orally or parenterally (for example, transrectally,intravenously, intramuscularly, and subcutaneously) to human beings andnon-humans, usually mammals (e.g., human beings, mice, rats, rabbits,dogs, cats, bovines, horses, pigs, and monkeys). The amount to beadministered (or dose) of the compound or the salt thereof of thepresent invention may suitably be selected according to the subject ofadministration, the age, body weight, sex, and condition (e.g., aperformance status, a condition of a disease, and a presence of acomplication) of the subject, the time (or period or schedule) ofadministration, the dosage form, the method (or route) ofadministration, and others.

The amount to be administered (or dose) to human beings is, for example,in an oral administration, usually about 0.01 to 1,000 mg a day,preferably about 0.1 to 700 mg a day, and more preferably about 0.2 to500 mg a day, in a free form of the compound or the salt thereof.Further, in a topically administering agent, the amount to beadministered to human beings is usually about 0.01 to 200 mg a day,preferably about 0.05 to 100 mg a day, and more preferably about 0.1 to80 mg a day, in a free form of the compound or the salt thereof.

EXAMPLES

The following examples are intended to describe this invention infurther detail and should by no means be interpreted as defining thescope of the invention.

In the formulae, R represents an alkyl group or an alkoxyalkyl group.

Example 1-1 Step 1-1-1 Ethyl 4-fluoro-3-nitrobenzoate

To a suspension of 4-fluoro-3-nitrobenzoic acid (150 g, 0.810 mol) inethanol (1000 ml), concentrated sulfuric acid (25 ml) was addeddropwise, and the mixture was heated under reflux for 8 hours. Afterbeing allowed to cool, the mixture was concentrated under a reducedpressure, and water was added thereto under stirring. The precipitatewas separated by filtration, washed with water and then subjected tothrough circulation drying to give the title compound (160 g, 93%) as ayellow solid.

¹H-NMR (DMSO-d₆) δ: 8.56 (dd, J=2.3, 7.3 Hz, 1H), 8.35-8.31 (m, 1H),7.76-7.71 (m, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H)

Mass, m/z: 213 (M⁺), 185, 168 (base)

Step 1-1-2 Ethyl 4-methylamino-3-nitrobenzoate

Ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.9 mmol) prepared in the Step1-1-1 was dissolved in methanol (40 ml), and triethylamine (10 ml,70.4=01) was added thereto. Under an ice cooling, a 40%methylamine-methanol solution (5.50 g, 70.4 mmol) was added to themixture. After the resulting mixture was stirred for one hour under anice cooling, ice water was added thereto. The precipitate was separatedby filtration and washed with water. The washed product was subjected tothrough circulation drying overnight to give the title compound (10.4 g,99%) as a yellow powder.

¹H-NMR (CDCl₃) δ: 8.87 (d, J=1.9 Hz, 1H), 8.33 (brs, 1H), 8.08 (dd,J=1.9, 9.2 Hz, 1H), 6.87-6.84 (m, 1H), 4.35 (q, J=6.9 Hz, 2H), 3.08 (d,J=5.0 Hz, 3H), 1.38 (t, J=6.9 Hz, 3H)

Mass, m/z: 224 (M⁺), 179, 105 (base)

Step 1-1-3 Ethyl 3-amino-4-methylaminobenzoate

Ethyl 4-methylamino-3-nitrobenzoate (6.80 g, 30.3 mmol) prepared in theStep 1-1-2 was dissolved in methanol (200 ml), and palladium 5% oncarbon (1.10 g) was added to the solution. The mixture was stirred undera hydrogen flow at a room temperature overnight. The mixture wasfiltered, and the filtrate was concentrated to give the title compound(4.85 g, 82%) as a light-brown powder.

¹H-NMR (CDCl₃) δ: 7.92 (dd, J=1.9, 8.5 Hz, 1H), 7.40 (d, J=1.9 Hz, 1H),6.58 (d, J=8.5 Hz, 1H), 4.31 (q, J=7.3 Hz, 2H), 3.99 (brs, 1H), 3.22(brs, 2H), 2.19 (s, 3H), 1.36 (t, J=7.3 Hz, 3H)

Mass, m/z: 194 (M⁺, base), 149

Step 1-1-4 Ethyl 1-methyl-1H-benzimidazole-5-carboxylate

Ethyl 3-amino-4-methylaminobenzoate (24.1 g, 124 mmol) in the Step 1-1-3was dissolved in formic acid (200 ml), and the solution was heated underreflux for 2 hours. After being cooled by ice, the solution wasneutralized with a 25% ammonia water. The solution was subjected toextraction with chloroform, and the extract was dried over anhydrousmagnesium sulfate and then concentrated. The concentrate was purified bysilica gel column chromatography (chloroform:methanol=20:1) to give thetitle compound (26.1 g, quantitative) as a light-purple powder.

¹H-NMR (CDCl₃) δ: 8.52 (d, J=1.5 Hz, 1H), 8.04 (dd, J=1.5, 8.5 Hz, 1H),7.92 (s, 1H), 7.39 (d, J=8.5 Hz, 1H), 4.40 (q, J=7.3 Hz, 2H), 3.86 (s,3H), 1.41 (t, J=7.3 Hz, 3H)

Mass, m/z: 204 (M⁺), 159 (base)

Step 1-1-5 (1-Methyl-1H-benzimidazol-5-yl)methanol

Under an argon gas flow, lithium aluminum hydride (9.70 g, 256 mmol) wassuspended in tetrahydrofuran (100 ml); and under an ice cooling, asolution (100 ml) of ethyl 1-methyl-1H-benzimidazole-5-carboxylate (26.1g, 128 mmol) prepared in the Step 1-1-4 in tetrahydrofuran was slowlyadded thereto. The mixture was stirred under an ice cooling for onehour. Under an ice cooling, a saturated sodium bicarbonate solution wasslowly added to the mixture. The precipitate was removed by filtration,and the residue was concentrated. The concentrate was dissolved inchloroform, and the solution was washed with a saturated sodiumbicarbonate solution and then concentrated. The concentrate was purifiedby silica gel column chromatography (chloroform:methanol=10:1 to 5:1) togive the title compound (11.4 g, 55%) as a light-red powder.

¹H-NMR (CDCl₃) δ: 7.85 (s, 1H), 7.77 (s, 1H), 7.37-7.34 (m, 2H), 4.80(s, 2H), 3.84 (s, 3H), 1.92 (brs, 1H)

Mass, m/z: 162 (M⁺), 133 (base)

Examples 1-2 to 1-6

The objective bicyclic compounds were obtained according to the sameprocedure as in Example 1-1 except that compounds shown in the followingtable were used instead of the 40% methylamine-methanol solution as aring-forming component or ethyl 4-fluoro-3-nitrobenzoate as a monocycliccompound.

TABLE 9 Ring- Mono- forming cyclic component compound Example ¹H-NMRMass, m/z Ethyl amine —

(DMSO-d₆) δ: 8.19 (s, 1H), 7.57 (d, J = 0.8 Hz, 1H), 7.53 (d, J = 8.5Hz, 1H), 7.22 (dd, J = 1.5, 8.5 Hz, 1H), 5.10 (t, J = 5.8 Hz, 1H), 4.59(d, J = 5.8 Hz, 2H), 4.26 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H)176 (M⁺), 147 (base) 1-Amino propane —

(DMSO-d₆) δ: 8.17 (s, 1H), 7.57 (s, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.22(dd, J = 1.2, 8.5 Hz, 1H), 5.09 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.8Hz, 2H), 4.19 (t, J = 6.9 Hz, 2H), 1.85- 1.76 (m, 2H), 0.83 (t, J = 7.3Hz, 3H) 190 (M⁺), 161 (base) Isopropyl amine —

(DMSO-d₆) δ: 8.27 (s, 1H), 7.57-7.54 (m, 2H), 7.23- 7.20 (m, 1H), 5.10(t, J = 5.8 Hz, 1H), 4.76-4.70 (m, 1H), 4.58 (d, J = 5.8 Hz, 2H) 1.53(d, J = 6.7 Hz, 6H) 232 (M⁺), 187 (base) — 4-Fluoro- 3-nitro- aceto-phenone

(DMSO-d₆) δ: 8.12 (s, 1H), 7.58 (d, J = 0.8 Hz, 1H), 7.47 (d, J = 8.5Hz, 1H), 7.27 (dd, J = 1.5, 8.5 Hz, 1H), 5.08 (d, J = 4.2 Hz, 1H),4.86-4.81 (m, 1H), 3.82 (s, 3H), 1.37 (d, J = 6.6 Hz, 3H) 176 (M⁺, base)2-Methoxy ethyl amine —

(DMSO-d₆) δ: 8.12 (s, 1H), 7.56 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.21(dd, J = 1.2, 8.5 Hz, 1H), 5.10 (t, J = 5.8 Hz, 1H), 4.58 (d, J = 5.8Hz, 2H), 4.39 (t, J = 5.4 Hz, 2H), 3.67 (t, J = 5.4 Hz, 2H), 3.22 (s,3H) 206 (M⁺), 161 (base)

In the formulae, R represents an alkyl group, and R′ represents an alkylgroup or an alkoxyalkyl group.

Example 2-1 Step 2-1-1 Ethyl 1,2-dimethyl-1H-benzimidazole-5-carboxylate

Ethyl 3-amino-4-methylaminobenzoate (1.00 g, 5.15 mmol) prepared in theStep 1-1-3 was dissolved in acetic anhydride (4 ml), and the mixture washeated under reflux for 19 hours. After being allowed to cool, themixture was neutralized with a saturated sodium bicarbonate solution andsubjected to extraction with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and then concentrated. The concentrate waspurified by silica gel column chromatography (chloroform:methanol=10:1)to give the title compound (1.15 g, quantitative) as a light-brown oilysubstance.

¹H-NMR (CDCl₃) δ: 8.39 (d, J=1.5 Hz, 1H), 7.98 (dd, J=1.5, 8.5 Hz, 1H),7.28 (d, J=8.5 Hz, 1H), 4.39 (q, J=6.9 Hz, 2H), 3.75 (s, 3H), 2.62 (s,3H), 1.41 (t, J=6.9 Hz, 3H)

Mass, m/z: 218 (M⁺), 173 (base)

Step 2-1-2 (1,2-dimethyl-1H-benzimidazol-5-yl)methanol

Ethyl 1,2-dimethyl-1H-benzimidazole-5-carboxylate prepared in the Step2-1-1 was used and subjected to the same procedure as in the Step 1-1-5to give the title compound.

¹H-NMR (DMSO-d₆) δ: 7.44 (d, J=0.7 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.14(dd, J=1.5, 8.5 Hz, 1H), 5.09 (t, J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H),3.71 (s, 3H), 2.50 (s, 3H)

Mass, m/z: 176 (M⁺), 147 (base)

Examples 2-2 to 2-4

The objective bicyclic compounds were obtained according to the sameprocedure as in Example 2-1 except that compounds shown in the followingtable were used instead of acetic anhydride as a ring-forming componentor ethyl 3-amino-4-methylaminobenzoate as a monocyclic compound.

TABLE 10 Ring-forming Mono-cyclic component compound Example ¹H-NMRMass, m/z Propionic anhydride —

(CDCl₃) δ: 7.67 (s, 1H), 7.30-7.27 (m, 2H), 4.77 (s, 2H), 3.72 (s, 3H),2.90 (q, J = 7.7 Hz, 2H), 1.44 (t, J = 7.7 Hz, 3H) 190 (M⁺, base), 161 —Ethyl 3-amino-4- ethyl amino- benzoate

(DMSO-d₆) δ: 7.45 (d, J = 0.8 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.14(dd, J = 1.5, 8.5 Hz, 1H), 5.06 (t, J = 5.8 Hz, 1H), 4.56 (d, J = 5.8Hz, 2H), 4.19 (q, J = 7.3 Hz, 2H), 2.51 (s, 3H), 1.28 (t, J = 7.3 Hz,3H) 190 (M⁺, base), 161 Methoxyacetic acid —

(DMSO-d₆) δ: 7.54 (d, J = 0.8 Hz, 1H), 7.48 (dd, J = 8.1 Hz, 1H), 7.23(dd, J = 1.5, 8.1 Hz, 1H), 4.68 (s, 2H), 4.58 (d, J = 5.8 Hz, 2H), 3.79(s, 3H), 3.32 (s, 3H) 206 (M⁺), 190 (base)

In the formulae, R represents a hydrogen atom, an alkyl group or ahydroxyl group; X represents CH₂, NH, O or S; and n is an integer of 1to 3.

Example 3-1 Step 3-1-1 Ethyl 3-nitro-4-piperidin-1-ylbenzoate

Ethyl 4-fluoro-3-nitrobenzoate (160 g, 0.752 mol) prepared in the Step1-1-1 was suspended in ethanol (500 ml). Triethylamine (91.4 g, 0.903mol) was added to the suspension, and under an ice cooling, piperidine(76.9 g, 0.903 mol) was slowly added thereto. After the mixture wasstirred at a room temperature for 2 hours, a saturated sodiumbicarbonate solution was added to the mixture, and the resulting mixturewas subjected to extraction with ethyl acetate. The ethyl acetate layerwas washed with a saturated sodium bicarbonate solution and a saturatedsaline solution in order, and then dried over anhydrous magnesiumsulfate and concentrated. The concentrate was purified by silica gelcolumn chromatography (n-hexane:ethyl acetate=4:1 to 3:1) to give thetitle compound (222 g, quantitative) as a poppy-red oily substance.

¹H-NMR (DMSO-d₆) δ: 8.26 (d, J=2.3 Hz, 1H), 7.98 (dd, J=2.3, 8.9 Hz,1H), 7.31 (d, J=9.2 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 3.13 (brs, 4H),1.60 (brs, 6H), 1.31 (t, J=7.3 Hz, 3H)

Mass, m/z: 278 (M⁺), 261 (base)

Step 3-1-2 Ethyl 3-amino-4-piperidin-1-ylbenzoate

Ethyl 3-nitro-4-piperidin-1-ylbenzoate (2.83 g, 10.2 mmol) prepared inthe Step 3-1-1 was dissolved in methanol (50 ml), and palladium 5% oncarbon (500 mg) was added to the solution. The mixture was stirred undera hydrogen flow at a room temperature overnight. The mixture wasfiltered, and the filtrate was concentrated to give the title compound(2.23 g, 90%) as a blackish-red solid.

¹H-NMR (CDCl₃) δ: 7.43 (dd, J=2.3, 8.1 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H),6.95 (d, J=8.1 Hz, 1H), 4.32 (q, J=7.3 Hz, 2H), 3.95 (brs, 2H),2.95-2.80 (m, 4H), 1.72-1.68 (m, 4H), 1.61-1.57 (m, 2H), 1.36 (t, J=7.3Hz, 3H)

Mass, m/z: 248 (M⁺, base)

Step 3-1-3 Ethyl1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate

Ethyl 3-amino-4-piperidin-1-ylbenzoate (5.38 g, 21.7 mmol) prepared inthe Step 3-1-2 was dissolved in formic acid (90%, 40 ml). Hydrogenperoxide solution (20 ml) was added to the solution, and the mixture washeated under reflux for 40 minutes. After being allowed to cool, themixture was neutralized with a saturated sodium bicarbonate solution anda 25% ammonia water and subjected to extraction with ethyl acetate. Theextract was dried over anhydrous magnesium sulfate and thenconcentrated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to give the title compound(3.94 g, 74%) as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 8.13 (d, J=1.2 Hz, 1H), 7.84 (dd, J=1.5, 8.1 Hz,1H), 7.57-7.54 (m, 1H), 4.32 (q, J=6.9 Hz, 2H), 4.16-4.13 (m, 2H),3.02-2.98 (m, 2H), 2.09-2.03 (m, 2H), 1.98-1.92 (m, 2H), 1.35 (t, J=6.9Hz, 3H)

Mass, m/z: 244 (M⁺), 199 (base)

Step 3-1-4(1,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-yl)methanol

Lithium aluminum hydride (1.97 g, 51.9 mmol) was suspended intetrahydrofuran (30 ml); and under an ice cooling, a solution (20 ml) ofethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-7-carboxylate(6.34 g, 26.0 mmol) prepared in the Step 3-1-3 in tetrahydrofuran wasslowly added thereto. After the mixture was stirred under an ice coolingfor one hour, a saturated sodium bicarbonate solution (5 ml) was slowlyadded to the mixture at the same temperature while paying attention tothe generation of heat. Further, ethyl acetate was slowly added to themixture. The mixture was allowed to cool to a room temperature andfiltered. The filtrate was thoroughly washed with chloroform. Thefiltrate was concentrated and purified by silica gel columnchromatography (chloroform:methanol=20:1 to 10:1) to give the titlecompound (4.20 g, 80%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.45 (d, J=0.7 Hz, 1H), 7.37 (d, J=8.1 Hz, 1H), 7.13(dd, J=1.2, 8.1 Hz, 1H), 5.08 (t, J=5.8 Hz, 1H), 4.57 (d, J=5.8 Hz, 2H),4.08-4.05 (m, 2H), 2.96-2.93 (m, 2H), 2.07-2.01 (m, 2H), 1.96-1.90 (m,2H)

Mass, m/z: 202 (M⁺, base), 185

Examples 3-2 to 3-7

The objective tricyclic compounds were obtained according to the sameprocedure as in Example 3-1 except that any one of N-containingmonocyclic compounds shown in the following table was used instead ofpiperidine.

TABLE 11 N-containing monocyclic compound Example ¹H-NMR Mass, m/zPyrrolidine

(DMSO-d₆) δ: 7.47 (s, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.12 (dd, J =1.2,8.1 Hz, 1H), 5.12 (br s, 1H), 4.57 (s, 2H), 4.08 (t, J = 6.9 Hz, 2H),2.95-2.91 (m, 2H), 2.67- 2.58 (m, 2H), 1.35 (t, J = 7.0 Hz, 3H) 188(M⁺), 171, 159 (base) Azepane

(DMSO-d₆) δ: 7.44 (s, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 1.2,8.1 Hz, 1H), 5.08-5.05 (m, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.12 (t, J =5.0 Hz, H), 3.01 (t, J = 5.8 Hz, 2H), 1.90-1.84 (m, 2H), 1.74-1.64 (m,4H) 216 (M⁺), 187 (base) 2-Methyl piperidine

(DMSO-d₆) δ: 7.44 (d, J = 0.8 Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.13(dd, J = 1.5, 8.5 Hz, 1H), 5.07 (t, J = 5.8 Hz, 1H), 4.67-4.59 (m, 1H),4.56 (d, J = 5.8 Hz, 2H), 3.01-2.94 (m, 1H), 2.91-2.82 (m, 1H), 2.18-2.09 (m, 1H), 2.04-1.95 (m, 1H), 1.92-1.84 (m, 2H), 1.42 (d, J = 6.4 Hz,3H) 216 (M⁺), 201, 187 (base) 4-Methyl piperidine

(DMSO-d₆) δ: 7.45 (d, J = 0.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.14(dd, J = 1.2, 8.1 Hz, 1H), 5.08 (t, J = 5.8 Hz, 1H), 4.57 (d, J = 5.4Hz, 2H), 4.25-4.20 (m, 1H), 3.97-3.90 (m, 1H), 3.07-3.02 (m, 1H),2.58-2.54 (m, 1H), 2.13-2.07 (m, 2H), 1.78-1.68 (m, 1H), 1.11 (d, J =6.6 Hz, 3H) 216 (M⁺), 187 (base) Morpholine

(DMSO-d₆) δ: 7.52 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.20 (dd, J = 1.5,8.5 Hz, 1H), 5.12 (t, J = 5.8 Hz, 1H), 4.94 (s, 2H), 4.59-4.58 (m, 2H),4.20-4.14 (m, 4H) 204 (M⁺), 187, 175 (base) 3-Hydroxy pyrrolidine

(DMSO-d₆) δ: 7.49 (s, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.13 (dd, J = 1.5,8.1 Hz, 1H), 5.62 (d, J = 4.6 Hz, 1H), 5.09 (t, J = 5.8 Hz, 1H),5.00-4.95 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 4.27 (dd, J = 5.4, 10.8 Hz,1H), 3.89 (dd, J = 2.3, 10.8 Hz, 1H), 3.25 (dd, J = 6.6, 17.0 Hz, 1H),2.77 (dd, J = 2.7, 17.0 Hz, 1H) 204 (M⁺), 175 (base)

Example 3-87-hydroxymethyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-ol

The title compound was obtained according to the same procedure as inExample 3-1 except that 4-hydroxypiperidine was used instead ofpiperidine.

¹H-NMR (DMSO-d₆) δ: 7.45 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.14 (dd,J=1.2, 8.1 Hz, 1H), 5.62 (d, J=3.5 Hz, 1H), 5.08 (t, J=5.8 Hz, 1H), 4.57(d, J=5.8 Hz, 2H), 4.29-4.23 (m, 1H), 4.12-4.07 (m, 2H), 3.13 (dd,J=4.2, 17.0 Hz, 1H), 2.87 (dd, J=5.4, 17.0 Hz, 1H), 2.18-1.91 (m, 2H)

Mass, m/z: 218 (M⁺, base)

In the formulae, R and R′ each represent a hydrogen atom or an alkylgroup.

Example 4-1 Step 4-1-1 Ethyl 4-amino-3-methylbenzoate

To a suspension of 4-amino-3-methylbenzoic acid (5.00 g, 33.1 mmol) inethanol (50 ml), concentrated sulfuric acid (5.00 ml) was slowly added.The mixture was heated under reflux for 3 hours. The solvent wasdistilled off under a reduced pressure. After the volume of the mixturewas approximately halved, the mixture was neutralized with a saturatedsodium bicarbonate solution. The mixture was subjected to extractionwith ethyl acetate, and the extract was dried over anhydrous magnesiumsulfate and then concentrated to give the title compound (5.87 g, 99%)as a light-brown solid.

¹H-NMR (CDCl₃) δ: 7.74 (d, J=2.3 Hz, 1H), 7.72 (d, J=1.9 Hz, 1H), 6.62(d, J=8.1 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 4.00 (brs, 2H), 2.17 (s, 3H),1.35 (t, J=7.3 Hz, 3H)

Mass, m/z: 179 (M⁺), 134 (base)

Step 4-1-2 Ethyl 1H-indazole-5-carboxylate

Ethyl 4-amino-3-methylbenzoate (12.6 g, 70.0 mmol) prepared in the Step4-1-1 and potassium acetate (7.20 g, 73.5 mmol) were suspended inchloroform (70 ml). Acetic anhydride (14.3 g, 140 mmol) was added to thesuspension, and the mixture was stirred for one hour. To the mixture,18-crown-6 (3.70 g, 14.0 mmol) and isoamyl nitrite (18.9 g, 161 mmol)were added, and the resulting mixture was heated under reflux for 21hours. After being allowed to cool, under an ice cooling the mixture wasrendered faintly alkaline with a saturated sodium bicarbonate solutionand a 25% ammonia water. The faintly alkalified mixture was subjected toextraction with chloroform, and the extract was dried over anhydrousmagnesium sulfate and then concentrated. The concentrate was purified bysilica gel column chromatography (n-hexane:ethyl acetate=1:1) to givethe title compound (4.06 g, 31%) as a light-brown powder and ethyl1-acetyl-1H-indazole-5-carboxylate.

The resulting ethyl 1-acetyl-1H-indazole-5-carboxylate was stirred in amixture of concentrated hydrochloric acid (15 ml), water (15 ml) andethanol (30 ml) for 15 hours at a room temperature. The resultingmixture was rendered faintly alkaline with a 25% ammonia water. Thefaintly alkalified mixture was subjected to extraction with chloroform.The extract was crystallized from n-hexane, and then the resultingcrystal was separated by filtration and dried to give the title compound(6.45 g, 48%) as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 13.38 (s, 1H), 8.49 (s, 1H), 7.92 (dd, J=1.5, 8.9Hz, 1H), 7.62 (d, J=8.9 Hz, 1H), 4.33 (q, J=7.3 Hz, 2H), 1.35 (t, J=7.3Hz, 3H)

Mass, m/z: 190 (M⁺), 145 (base)

Step 4-1-3 Ethyl 1-methyl-1H-indazole-5-carboxylate and ethyl2-methyl-2H-indazole-5-carboxylate

Ethyl 1H-indazole-5-carboxylate (1.62 g, 10.0 mmol) obtained in the Step4-1-2 was dissolved in tetrahydrofuran (20 ml). To the solution, 60%sodium hydride suspension in oil (420 mg, 10.5 mmol) was added, and themixture was stirred for 10 minutes. Methyl iodide (1.49 g, 10.5 mmol)was added dropwise to the mixture. The resulting mixture was stirred ata room temperature overnight. Ethyl acetate was added thereto, and theresulting mixture was washed with a saturated sodium bicarbonatesolution and then dried over anhydrous magnesium sulfate andconcentrated. The concentrate was purified by silica gel columnchromatography (n-hexane:ethyl acetate=3:1) to firstly give ethyl1-methyl-1H-indazole-5-carboxylate (light-brown solid, 0.80 g, 39%) andto secondly give ethyl 2-methyl-2H-indazole-5-carboxylate (light-brownsolid, 0.60 g, 29%).

4-1-3-A: Ethyl 1-methyl-1H-indazole-5-carboxylate

¹H-NMR (CDCl₃) δ: 8.51 (d, J=1.5 Hz, 1H), 8.08 (d, J=1.2 Hz, 1H), 8.07(dd, J=1.5, 8.9 Hz, 1H), 7.39 (dd, J=0.8, 8.9 Hz, 1H), 4.40 (q, J=6.9Hz, 2H), 4.10 (s, 3H), 1.42 (t, J=6.9 Hz, 3H)

Mass, m/z: 204 (M⁺), 159 (base)

4-1-3-B: Ethyl 2-methyl-2H-indazole-5-carboxylate

¹H-NMR (CDCl₃) δ: 8.48 (s, 1H), 8.03 (s, 1H), 7.90 (dd, J=1.5, 9.2 Hz,1H), 7.68 (d, J=8.9 Hz, 1H), 4.38 (q, J=7.3 Hz, 2H), 4.24 (s, 3H), 1.40(t, J=7.3 Hz, 3H)

Mass, m/z: 204 (M⁺), 159 (base)

Step 4-1-4 (1-Methyl-1H-indazol-5-yl)methanol

Lithium aluminum hydride (300 mg, 7.83 mmol) was suspended intetrahydrofuran (20 ml); and under an ice cooling, a solution (10 ml) ofethyl 1-methyl-1H-indazole-5-carboxylate (800 mg, 3.92 mmol) prepared inthe Step 4-1-3-A in tetrahydrofuran was slowly added thereto. After themixture was stirred under an ice cooling for 30 minutes, 5 drops of asaturated sodium bicarbonate solution were slowly added to the mixture.Ethyl acetate was added to the mixture, and 5 drops of a saturatedsodium bicarbonate solution was further added thereto. The precipitatewas removed by filtration, and the filtrate was concentrated. Theconcentrate was purified by silica gel column chromatography(n-hexane:ethyl acetate=1:1) to give the title compound (420 mg, 66%) asa light-brown powder.

¹H-NMR (CDCl₃)₆: 7.95 (s, 1H), 7.69 (s, 1H), 7.43-7.37 (m, 2H), 4.78 (d,J=5.8 Hz, H), 4.07 (s, 3H)

Mass, m/z: 162 (M⁺, base)

Example 4-2 Step 4-1-5 (2-Methyl-2H-indazol-5-yl)methanol

Ethyl 2-methyl-2H-indazole-5-carboxylate prepared in the Step 4-1-3-Bwas used and subjected to the same procedure as in the Step 4-1-4 togive the title compound.

¹H-NMR (DMSO-d₆) δ: 8.25 (s, 1H), 7.57 (d, J=1.5 Hz, 1H), 7.53 (d, J=8.9Hz, 1H), 7.18 (dd, J=1.5, 8.9 Hz, 1H), 5.10 (t, J=5.8 Hz, 1H), 4.52 (d,J=5.8 Hz, 2H), 4.14 (s, 3H)

Mass, m/z: 162 (M⁺, base)

Examples 4-3 to 4-7

According to the production processes shown in the following table,compounds shown in the following table were used instead of methyliodide as an alkylating component or 4-amino-3-methylbenzoic acid as amonocyclic compound to give the objective bicyclic compounds.

TABLE 12 Mono- Pro- Alkylating cyclic duction component compound processExample ¹H-NMR Mass, m/z Ethyl iodide — Example 4-1

(DMSO-d₆) δ: 8.00 (d, J = 1.8 Hz, 1H), 7.65 (d, J = 0.8 Hz, 1H), 7.60(d, J = 8.5 Hz, 1H), 7.35 (dd, J = 1.5, 8.9 Hz, 1H), 4.58 (s, 2H), 4.42(q, J = 7.3 Hz, 2H), 1.38 (t, J = 7.3 Hz, 3H) 176 (M⁺, base), 161 Ethyliodide — Example 4-2

(DMSO-d₆) δ: 8.30 (d, J = 0.8 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.54(d, J = 8.9 Hz, 1H), 7.18 (dd, J = 1.5, 8.9 Hz, 1H), 5.10 (t, J = 5.4Hz, 1H), 4.53 (d, J = 5.4 Hz, 2H), 4.43 (q, J = 7.3 Hz, 2H), 1.50 (t, J= 7.3 Hz, 3H) 176 (M⁺, base), 147 — 3-Amino-4-methyl benzoic acidExample 4-1 Example 4-2

(DMSO-d₆) δ: 8.25 (s, 1H), 7.61 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 1.2Hz, 1H), 6.98 (dd, J = 1.2, 8.9 Hz, 1H), 5.16 (t, J = 5.8 Hz, 1H), 4.56(d, J = 5.8 Hz, 2H), 4.14 (s, 2H) 162 (M⁺, base) Ethyl iodide3-Amino-4-methyl benzoic acid Example 4-1 Example 4-2

(DMSO-d₆) δ: 8.30 (d, J = 0.8 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.48(d, J = 0.8 Hz, 1H), 6.98 (dd, J = 1.2, 8.5 Hz, 1H), 5.16 (t, J = 5.8Hz, 1H), 4.55 (d, J = 5.8 Hz, 2H), 4.43 (q, J = 7.3 Hz, 2H), 1.50 (t, J= 7.3 Hz, 3H) 176 (M⁺, base) Ethyl iodide 3-Amino-4-methyl benzoic acidExample 4-1

(DMSO-d₆) δ: 7.98 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.08(d, J = 8.1 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 4.64 (d, J = 5.8 Hz, 2H),4.41 (q, J = 7.3 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H) 176 (M⁺) (base), 161,147, 131

In the formulae, R represents an alkyl group.

Example 5-1 Step 5-1-1 Ethyl 1-ethyl-5-benzotriazolecarboxylate

Ethyl 3-amino-4-ethylaminobenzoate (1.80 g, 9.27 mmol) prepared in thesame manner as in the Step 1-1-3 was dissolved in acetic acid (5 ml),and under an ice cooling sodium nitrite (1.28 g, 18.5 mmol) was added tothe solution little by little. The mixture was stirred for 10 minutesunder a water cooling. The mixture was cooled by ice again andneutralized with a 25% ammonia water. Thereafter, ethyl acetate wasadded to the mixture, and the resulting mixture was washed with asaturated saline solution and water in order. The washed mixture wasdried over anhydrous magnesium sulfate and then concentrated. Theresidue was purified by silica gel column chromatography (n-hexane:ethylacetate=3:1 to 1:1) to give the title compound (1.40 g, 69%) as a brownpowder.

¹H-NMR (CDCl₃) δ: 8.63 (s, 1H), 8.10 (dd, J=1.5, 8.9 Hz, 1H), 8.02 (d,J=8.6 Hz, 1H), 4.49 (q, J=7.3 Hz, 2H), 4.38 (q, J=6.9 Hz, 2H), 1.54 (t,J=7.3 Hz, 3H), 1.37 (t, J=6.9 Hz, 3H) Mass, m/z: 219 (M⁺), 118 (base)

Step 5-1-2 (1-Ethyl-1H-benzotriazol-5-yl)methanol

Ethyl 1-ethyl-5-benzotriazolecarboxylate prepared in the Step 5-1-1 wasused and subjected to the same procedure as in the Step 1-1-5 to givethe title compound.

¹H-NMR (CDCl₃) δ: 8.00 (d, J=1.2 Hz, 1H), 7.52 (t, J=1.2 Hz, 2H), 4.85(d, J=3.1 Hz, 1H), 4.68 (q, J=7.3 Hz, 2H), 1.62 (t, J=7.3 Hz, 3H)

Mass, m/z: 177 (M⁺), 104 (base)

Example 6-1 Step 6-1-1 Ethyl 2,3-dimethylquinoxaline-6-carboxylate

Ethyl 3,4-diaminobenzoate (500 mg, 2.77 mmol) and diacetyl (238 mg, 2.77mmol) were dissolved in ethanol (20 ml), and the mixture was heatedunder reflux. One hour after, diacetyl (30 mg) was added thereto, andthe mixture was heated under reflux. After the mixture was heated underreflux for 2.5 hours in total, the reaction solution was poured intowater, and the precipitate was separated by filtration and washed withwater. By through circulation drying for 15 hours, the title compound(650 mg, quantitative) as a light-brown powder was obtained.

¹H-NMR (DMSO-d₆) δ: 8.52 (d, J=1.5 Hz, 1H), 8.19 (dd, J=1.9, 8.5 Hz,1H), 8.07 (d, J=8.5 Hz, 1H), 4.40 (q, J=6.9 Hz, 2H), 2.72 (s, 3H), 2.72(s, 3H)

Mass, m/z: 230 (M⁺), 185 (base)

Step 6-1-2 (2,3-Dimethylquinoxalin-6-yl)methanol

Ethyl 2,3-dimethylquinoxaline-6-carboxylate prepared in the Step 6-1-1used and subjected to the same procedure as in the Step 1-1-5 to givethe title compound.

¹H-NMR (DMSO-d₆) δ: 8.31 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.86 (d, J=1.2Hz, 1H), 7.66 (dd, J=1.9, 8.5 Hz, 1H), 6.29 (brs, 1H), 4.71 (d, J=5.8Hz, 1H), 2.67 (s, 3H), 2.67 (s, 3H)

Mass, m/z: 188 (M⁺), 159 (base)

In the formulae, R represents a carbocyclic (homocyclic) or heterocyclicgroup which may have a substituent (such as a halogen atom, an alkylgroup, or an alkoxy group); and R′ represents a hydrogen atom, an alkylgroup, a haloalkyl group or a cycloalkyl group.

Example 7-1 Step 7-1-1 4-Chloro-2-methoxybenzamide

Thionyl chloride (262 g, 2.20 mol) was added to4-chloro-2-methoxybenzoic acid (155 g, 0.831 mmol), and the mixture washeated under reflux for 2 hours. After thionyl chloride was distilledoff under a reduced pressure, tetrahydrofuran was added thereto and theresidue was dissolved. Under an ice cooling, a 25% ammonia water (1.0 L)was slowly added thereto. The resulting mixture was stirred at a roomtemperature for 18 hours. The precipitate was separated by filtration,washed with water and then subjected to through circulation drying togive the title compound (147 g, 95%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.79 (d, J=8.1 Hz, 1H), 7.58 (d, J=12.3 Hz, 1H),7.22 (d, J=1.9 Hz, 1H), 3.91 (s, 3H)

Mass, m/z: 187&185 (M⁺), 165 (base)

Step 7-1-2 4-Chloro-2-methoxythiobenzamide

In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (9.40 g, 50.6mmol) prepared in the Step 7-1-1 and Lawesson's reagent (10.2 g, 25.3mmol) were suspended, and the suspension was heated under reflux for 2hours. After the suspension was allowed to cool, a saturated sodiumbicarbonate solution was added to the suspension to stop the reaction.Then the reaction mixture was subjected to extraction with ethylacetate, and the extract was dried over anhydrous magnesium sulfate andthen concentrated. The concentrate was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) to give the title compound(6.63 g, 65%) as a yellow powder.

¹H-NMR (CDCl₃) δ: 8.89 (brs, 1H), 8.60 (d, J=8.5 Hz, 1H), 7.96 (brs,1H), 7.04 (dd, J=1.9, 8.5 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 3.97 (s, 3H)

Mass, m/z: 201&203 (M⁺), 168 (base)

Step 7-1-3 Ethyl2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylate

In ethanol (50 ml), 4-chloro-2-methoxythiobenzamide (4.00 g, 20.0 mmol)prepared in the Step 7-1-2 was suspended, and ethyl 2-chloroacetoacetate(3.62 g, 22.0 mmol) was added to the suspension. The mixture was heatedunder reflux overnight. After the mixture was allowed to cool, thesolvent was distilled off under a reduced pressure, and ethyl acetateand a saturated sodium bicarbonate solution were added to the mixture.The resulting mixture was subjected to extraction with ethyl acetate.The extract was dried over anhydrous magnesium sulfate and thenconcentrated. The residue was suspended in ethyl acetate-n-hexane (ethylacetate:n-hexane=1:1) and separated by filtration. The separated productwas washed with the same solvent and dried under a reduced pressure togive the title compound (4.84 g, 78%) as a light-yellow powder.

¹H-NMR (DMSO-d₆) δ: 8.31 (d, J=8.9 Hz, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.20(dd, J=1.9, 8.5 Hz, 1H), 4.31 (q, J=7.3 Hz, 2H), 4.09 (s, 3H), 2.70 (s,3H), 1.32 (t, J=7.3 Hz, 3H)

Mass, m/z: 311 (M⁺), 71 (base)

Step 7-1-4 2-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid

Ethyl 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylate (4.83g, 15.5 mmol) prepared in the Step 7-1-3 was suspended in ethanol (30ml), 1 mol/l of sodium hydroxide (30 ml) was added thereto, and themixture was heated under reflux for 1.5 hours. After being allowed tocool, the mixture was neutralized with hydrobromic acid, then separatedby filtration and washed with water. The washed product was subjected tothrough circulation drying to give the title compound (4.28 g, 97%) as awhite powder.

¹H-NMR (DMSO-d₆) δ: 8.29 (d, J=8.5 Hz, 1H), 7.38 (d, J=1.9 Hz, 1H), 7.19(dd, J=1.9, 8.5 Hz, 1H), 4.08 (s, 3H), 2.67 (s, 3H)

Mass, m/z: 283&285 (M⁺), 144 (base)

Examples 7-2 to 7-25 and 7-27 to 7-41

The objective compounds were obtained according to the same procedure asin Example 7-1 except that compounds shown in the following table wereused instead of 4-chloro-2-methoxybenzoic acid as a carboxylic acidcomponent or ethyl 2-chloroacetoacetate as a ring-forming component.

TABLE 13 Ring- Carboxylic forming acid compo- component nent Example¹H-NMR Mass, m/z 2-Fluoro benzoic acid —

(DMSO-d₆) δ: 13.44 (br s, 1H), 8.26 (dt, J = 1.5, 7.7 Hz, 1H), 7.64-7.58 (m, 1H), 7.49-7.38 (m, 2H), 2.71 (s, 3H) 237 (M⁺), 71 (base)3-Fluoro benzoic acid —

(DMSO-d₆) δ: 13.45 (br s, 1H), 7.84 (dd, J = 0.8, 1.5 Hz, 1H), 7.82-7.79 (m, 1H), 7.77-7.55 (m, 1H), 7.42-7.37 (m, 1H), 2.68 (s, 3H) 237(M⁺, base) 4-Fluoro benzoic acid —

(DMSO-d₆) δ: 13.38 (br s, 1H), 8.07- 8.01 (m, 2H), 7.39-7.33 (m, 2H),2.67 (s, 3H) 237 (M⁺, base) 2-Chloro- 4-fluoro benzoic acid —

(DMSO-d₆) δ: 13.46 (br s, 1H), 8.33 (dd, J = 6.6, 8.9 Hz, 1H), 7.71 (dd,J = 2.7, 8.9 Hz, 1H), 7.46- 7.41 (m, 1H), 2.70 (s, 3H) 271 (M⁺, base)4-Fluoro- 2-methyl benzoic acid —

(DMSO-d₆) δ: 7.88 (dd, J = 5.8, 8.5 Hz, 1H), 7.29 (dd, J = 2.7, 10.0 Hz,1H), 7.19 (dt, J = 2.7, 8.5 Hz, 1H), 2.68 (s, 3H), 2.57 (s, 3H) 251 (M⁺,base) 4-Chloro- 2-methyl benzoic acid —

(DMSO-d₆) δ: 7.86 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.41(dd, J = 2.3, 8.5 Hz, 1H), 2.69 (s, 3H), 2.57 (s, 3H) 267 (M⁺, base)2-Methoxy benzoic acid —

(DMSO-d₆) δ: 8.32 (dd, J = 1.9, 8.1 Hz, 1H), 7.56-7.51 (m, 1H), 7.28 (d,J = 8.1 Hz, 1H), 7.15-7.11 (m, 1H), 4.05 (s, 3H), 2.68 (s, 3H) 249 (M⁺),144, 71 (base)

TABLE 14 Ring- Carboxylic forming acid compo- component nent Example¹H-NMR Mass, m/z 2-Methyl benzoic acid —

(DMSO-d₆) δ: 7.81 (d, J = 7.7 Hz, 1H), 7.45-7.33 (m, 3H), 2.70 (s, 3H),2.56 (s, 3H) 233 (M⁺, base) 3-Methyl benzoic acid —

(DMSO-d₆) δ: 7.80 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.42-7.34 (m, 2H),2.67 (s, 3H), 2.39 (s, 3H) 233 (M⁺), 118 (base) 4-Methyl benzoic acid —

(DMSO-d₆) δ: 7.87 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 2.67(s, 3H), 2.37 (s, 3H) 233 (M⁺), 118 (base) 2-Ethyl benzoic acid —

(DMSO-d₆) δ: 7.66 (d, J = 7.7 Hz, 1H), 7.47 (dt, J = 1.2, 7.7 Hz, 1H),7.41 (dd, J = 1.2, 7.7 Hz, 1H), 7.35-7.31 (m, 1H), 2.93 (q, J = 7.7 Hz,2H), 2.69 (s, 3H), 1.15 (t, J = 7.7 Hz, 3H) 247 (M⁺, base), 2014-Fluoro- 2-methoxy benzoic acid —

(DMSO-d₆) δ: 13.17 (br s, 1H), 8.34 (dd, J = 6.9, 9.0 Hz, 1H), 7.22 (dd,J = 2.7, 11.2 Hz, 1H), 6.98 (dt, J = 2.7, 8.9 Hz, 1H), 4.06 (s, 3H),2.67 (s, 3H) 267 (M⁺, base) 2-Methoxy- 4-methyl benzoic acid —

(DMSO-d₆) δ: 8.18 (d, J = 8.5 Hz, 1H), 7.09 (s, 1H), 6.94 (d, J = 8.5Hz, 1H), 4.02 (s, 3H), 2.66 (s, 3H), 2.50 (s, 3H) 263 (M⁺), 71 (base)2,4- Dimethoxy benzoic acid —

(DMSO-d₆) δ: 8.23 (d, J = 8.5 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.71(dd, J = 2.3, 8.8 Hz, 1H), 4.04 (s, 3H), 3.87 (s, 3H), 2.65 (s, 3H) 279(M⁺, base), 233

TABLE 15 Ring- Carboxylic forming acid compo- component nent Example¹H-NMR Mass, m/z 2,4-Dimethyl benzoic acid —

(DMSO-d₆) δ: 7.73 (d, J = 8.1 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 8.1Hz, 1H), 2.68 (s, 3H), 2.54 (s, 3H), 2.50 (s, 3H) 247 (M⁺, base)2,3-Dihydro benzofuran- 7-carboxylic acid —

(DMSO-d₆) δ: 13.18 (br s, 1H), 7.95 (dd, J = 1.2, 8.1 Hz, 1H), 7.40 (dd,J = 1.2, 7.3 Hz, 1H), 6.99 (dd, J = 7.3, 8.1 Hz, 1H), 4.81 (t, J = 8.9Hz, 2H), 3.30 (t, J = 8.9 Hz, 2H), 2.68 (s, 3H) 261 (M⁺, base)2,3-Dihydro benzofuran- 5-carboxylic acid —

(DMSO-d₆) δ: 13.19 (br s, 1H), 7.86 (d, J = 1.5 Hz, 1H), 7.76 (dd, J =1.9, 8.5 Hz, 1H), 6.88 (dd, J = 8.5 Hz, 1H), 4.63 (t, J = 8.9 Hz, 2H),3.28-3.24 (m, 2H), 2.64 (s, 3H) 261 (M⁺, base) 2-Methyl cyclohexylcarboxylic acid —

(DMSO-d₆) δ: 13.11 (br s, 1H), 2.58 (s, 3H), 1.90-1.86 (m, 1H),1.80-1.60 (m, 4H), 1.52-1.28 (m, 4H), 1.12-1.06 (m, 1H), 0.75-0.73 (m,3H) 239 (M⁺), 157 (base) Adamantane- 1-carboxylic acid —

(DMSO-d₆) δ: 2.58 (s, 3H), 2.06 (s, 3H), 1.96 (d, J = 3.1 Hz, 6H),1.80-1.65 (m, 6H) 277 (M⁺, base) 2-Furan carboxylic acid —

(CDCl₃) δ: 7.57 (d, J = 1.2 Hz, 1H), 7.15 (dd, J = 3.5 Hz, 1H), 6.56(dd, J = 1.5, 3.5 Hz, 1H), 2.78 (s, 3H) 209 (M⁺, base) 3-Furancarboxylic acid —

(DMSO-d₆) δ: 13.30 (br s, 1H), 8.48 (s, 1H), 7.86-7.85 (m, 1H), 6.97-6.97 (m, 1H), 2.64 (s, 3H) 209 (M⁺, base)

TABLE 16 Carboxylic Ring- acid forming component component Example¹H-NMR Mass, m/z 2-Thiophene carboxylic acid — Example 7-23  

(DMSO-d₆) δ: 13.41 (br s, 1H), 7.81 (dd, J = 0.8, 5.4 Hz, 1H), 7.78 (dd,J = 1.2, 3.9 Hz, 1H), 7.20 (dd, J = 3.9, 5.0 Hz, 1H), 2.62 (s, 3H) 225(M⁺, base) 3-Chloro thiophene- 2-carboxylic acid — Example 7-24  

(DMSO-d₆) δ: 13.46 (br s, 1H), 7.93 (d, J = 5.4 Hz, 1H), 7.30 (d, J =5.4 Hz, 1H), 2.65 (s, 3H) 259 (M⁺),  71 (base) 5-Chloro thiophene-2-carboxylic acid — Example 7-25  

(DMSO-d₆) δ: 13.43 (br s, 1H), 7.70 (d, J = 4.2 Hz, 1H), 7.25 (d, J =3.9 Hz, 1H) 259 (M⁺),  71 (base) 2-Methoxy benzoic acid 2-Chloro- 3-oxopentanoic acid Example 7-27  

(DMSO-d₆) δ: 13.15 (br s, 1H), 8.34 (dd, J = 1.9, 8.1 Hz, 1H), 7.55-7.51 (m, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.15-7.11 (m, 1H), 4.05 (s, 3H),3.12 (q, J = 7.7 Hz, 2H), 1.27 (t, J = 7.7 Hz, 3H) 263 (M⁺, base) —2-Chloro- 3-oxo pentanoic acid Example 7-28  

(DMSO-d₆) δ: 13.21 (br s, 1H), 8.32 (d, J = 8.5 Hz, 1H), 7.39 (d, J =2.3 Hz, 1H), 7.20 (dd, J = 1.9, 8.5 Hz, 1H), 4.08 (s, 3H), 3.11 (q, J =7.7 Hz, 2H), 1.26 (t, J = 7.7 Hz, 3H) 297 (M⁺, base) 2,4-Dimethylbenzoic acid 2-Chloro- 3-oxo pentanoic acid Example 7-29  

(DMSO-d₆) δ: 7.73 (d, J = 7.7 Hz, 1H), 7.21 (s, 1H), 7.16 (d, J = 7.7Hz, 1H), 3.12 (q, J = 7.7 Hz, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 1.26 (t,J = 7.7 Hz, 3H) 261 (M⁺, base) 4-Fluoro- 2-methyl benzoic acid 2-Chloro-3-oxo pentanoic acid Example 7-30  

(DMSO-d₆) δ: 13.38 (br s, 1H), 7.88 (dd, J = 5.8, 8.9 Hz, 1H), 7.29 (dd,J = 2.7, 10.0 Hz, 1H), 7.19 (dt, J = 2.7, 8.5 Hz, 1H), 3.12 (q, J = 7.3Hz, 2H), 2.57 (s, 3 H), 1.27 (t, J = 7.3 Hz, 3H) 265 (M⁺, base)

TABLE 17 Carboxylic Ring- acid forming component component Example¹H-NMR Mass, m/z 2-Methoxy- 4-methyl benzoic acid 2-Chloro- 3-oxopentanoic acid Example 7-31  

(DMSO-d₆) δ: 13.08 (br s, 1H), 8.21 (dd, J = 7.7 Hz, 1H), 7.11 (s, 1 H),6.95 (d, J = 7.7 Hz, 1H), 4.03 (s, 3H), 3.10 (q, J = 7.7 Hz, 2H), 2.39(s, 3H), 1.26 (t, J = 7.7 Hz, 3H) 277 (M⁺, base) — Methyl 2-chloro-3-oxo propionate Example 7-32  

(DMSO-d₆) δ: 13.45 (br s, 1H), 8.45 (s, 1H), 8.33 (d, J = 8.5 Hz, 1H),7.43 (d, J = 1.9 Hz, 1H), 7.22 (dd, J = 1.9, 8.5 Hz, 1H), 4.10 (s, 3H)269 (M⁺), 169 (base) 2-Methoxy benzoic acid Methyl 2-chloro-3-oxopropionate Example 7-33  

(DMSO-d₆) δ: 13.37 (br s, 1H), 8.43 (s, 1H), 8.34 (dd, J = 1.9, 8.1 Hz,1H), 7.57-7.53 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.17-7.12 (m, 1H),4.07 (s, 3H) 235 (M⁺), 189 (base) — Ethyl 2-chloro-3- oxohexanoateExample 7-34  

(CDCl₃) δ: 8.41 (d, J = 8.5 Hz, 1H), 7.08 (dd, J = 1.9, 8.5 Hz, 1H),7.03 (d, J = 1.9 Hz, 1H), 4.05 (s, 3H), 3.18 (t, J = 7.7 Hz, 2H),1.87-1.78 (m, 2H), 1.02 (t, J= 7.7 Hz, 3H) 311 (M⁺), 283 (base)2,4-Dimethyl benzoic acid Ethyl 2-chloro-3- oxohexanoate Example 7-35  

(CDCl₃) δ: 7.70 (d, J = 7.7 Hz, 1H), 7.12-7.04 (m, 2H), 3.19 (t, J = 7.3Hz, 2H), 2.58 (s, 3H), 2.36 (s, 3H), 1.88-1.76 (m, 2H), 1.02 (t, J = 7.3Hz, 3H). 275 (M⁺), 247 (base) 2,4-Dimethyl benzoic acid Methyl2-chloro-3- cyclopropyl- 3-oxo propionate Example 7-36  

(CDCl₃) δ: 7.67-7.62 (m, 1H), 7.10- 6.85 (m, 2H), 3.10-3.03 (m, 1 H),2.35 (s, 3H), 2.34 (s, 3 H), 1.25-1.18 (m, 2H), 1.14- 1.07 (m, 2H) 273(M⁺, base) 4-Chloro- 2-methyl benzoic acid Ethyl 2-chloro-4,4,4-trifluoro- 3-oxobutyrate Example 7-37  

(CDCl₃) δ: 7.80 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.31 (dd,J = 1.9, 8.1 Hz, 1H), 2.63 (s, 3H) 273 (M⁺, base)

TABLE 18 Carboxylic Ring- acid forming component component Example¹H-NMR Mass, m/z 2,4-Difluoro benzoic acid — Example 7-38  

(DMSO-d₆) δ: 13.44 (br s, 1H), 8.30 (dt, J = 6.6, 8.9 Hz, 1H), 7.54(ddd, J = 2.3, 8.9, 11.9 Hz, 1H), 7.30 (dt, J = 2.7, 8.5 Hz, 1H), 2.70(s, 3H) 255 (M⁺) (base), 140, 116 3-Methyl picolinic acid — Example 7-39 

(DMSO-d₆) δ: 8.51 (dd, J = 1.5, 4.6 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1H),7.42 (dd, J = 4.6, 7.7 Hz, 1H), 2.74 (s, 3H), 2.69 (s, 3H) 234 (M⁺,base) 4-Fluoro- 2-methoxy benzoic acid 2-Chloro- 3-oxo pentanoic acidExample 7-40  

(DMSO-d₆) δ: 8.36 (dd, J = 6.9, 8.9 Hz, 1H), 7.21 (dd, J = 2.3, 11.2 Hz,1H), 6.98 (dt, J = 2.3, 8.5 Hz, 1H), 4.06 (s, 3 H), 3.11 (q, J = 7.7 Hz,2H), 1.28 (t, J = 7.7 Hz, 3H) 281 (M⁺, base) 4-Chloro- 2-methyl benzoicacid 2-Chloro- 3-oxo pentanoic acid Example 7-41  

(DMSO-d₆) δ: 13.40 (br s, 1 H), 7.86 (d, J = 8.5 Hz, 1H), 7.51 (d, J =1.9 Hz, 1H), 7.41 (dd, J = 1.9, 8.5 Hz, 1H), 3.12 (q, J = 7.7 Hz, 2H),2.57 (s, 3 H), 1.26 (t, J = 7.7 Hz, 3H) 281 (M⁺, base)

Example 7-26 2,4-Dimethylthiazole-5-carboxylic acid

The title compound was obtained according to the same procedure as inExample 7-1 except that thioacetamide was used instead of4-chloro-2-methoxythiobenzamide.

¹H-NMR (DMSO-d₆) δ: 13.13 (brs, 1H), 2.62 (s, 3H), 2.56 (s, 3H)

Mass, m/z: 157 (M⁺, base)

In the formulae, R represents a carbocyclic (homocyclic) or heterocyclicgroup which may have a substituent (such as a halogen atom, an alkylgroup, a haloalkyl group, an alkoxy group, an amino group, or anN-alkyl-substituted amino group); and R′ represents a hydrogen atom, analkyl group or an aralkyl group.

Example 8-1 Step 8-1-1 Ethyl 4-(2,4-dichlorophenyl)-2,4-dioxobutyrate

A 20% sodium ethoxide-ethanol solution (17 g) was added totetrahydrofuran (100 ml), and the mixture was cooled to 0° C. It took 60minutes to dropwise add a solution of 2′,4′-dichloroacetophenone (9.45g) and diethyl oxalate (7.30 g) in tetrahydrofuran (100 ml) to themixture. After the completion of the dropping, the mixture was allowedto warm to a room temperature and stirred for 2 hours. To the mixture,2-N hydrochloric acid (200 ml) and chloroform (200 ml) were added. Theorganic layer was collected by separation and dried over anhydrousmagnesium sulfate, and the solvent was distilled off. Thus, the titlecompound (11.3 g, 78%) as a light-brown oily substance was obtained.¹H-NMR (DMSO-d₆) δ: 7.85-7.74 (m, 1H), 7.70-7.62 (m, 1H), 7.58-7.55 (m,2H), 6.53 (brs, 1H), 4.29-4.21 (m, 2H), 1.29-1.25 (m, 3H)

Mass, m/z: 288 (M⁺), 215 (base)

Step 8-1-2 Ethyl5-(2,4-dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylate and ethyl5-(2,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylate

Ethyl 4-(2,4-dichlorophenyl)-2,4-dioxobutyrate (11 g, 38 mmol) was addedto ethanol (50 ml), and methylhydrazine (1.84 g, 40 mmol) was addedthereto at a room temperature under stirring. After the mixture wasstirred for 60 minutes, ethanol was distilled off. To the residue,chloroform (300 ml) and water (200 ml) were added. The organic layer wascollected by separation, dried over anhydrous magnesium sulfate, and thesolvent was distilled off. Thus, 13 g of the residue was obtained. Theresidue was separated by silica gel column (ethyl acetate:n-hexane=5:1)to give ethyl 5-(2,4-dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylate(5.01 g, 45%) as a first eluate and ethyl5-(2,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylate (1.92 g, 17%)as a second eluate.

8-1-2-A: Ethyl 5-(2,4-dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylate

¹H-NMR (DMSO-d₆) δ: 7.83 (d, J=8.5 Hz, 1H), 7.73 (d, J=1.9 Hz, 1H), 7.51(dd, J=1.9, 8.5 Hz, 1H), 7.31 (s, 1H), 4.34 (q, J=7.3 Hz, 2H), 4.17 (s,3H), 1.33 (t, J=7.3 Hz, 3H)

Mass, m/z: 298 (M⁺), 55 (base)

8-1-2-B: Ethyl 5-(2,4-dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylate

¹H-NMR (DMSO-d₆) δ: 7.87 (d, J=1.9 Hz, 1H), 7.62-7.56 (m, 2H), 6.86 (s,1H), 4.29 (q, J=6.9 Hz, 2H), 3.72 (s, 3H), 1.30 (t, J=6.9 Hz, 3H)

Mass, m/z: 298 (M⁺), 226 (base)

Step 8-1-3 5-(2,4-Dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylic acid

Ethyl 5-(2,4-dichlorophenyl)-2-methyl-2H-pyrazole-3-carboxylate (2.98 g)was added to ethanol (50 ml), and sodium hydroxide (5.0 g) was addedthereto at a room temperature under stirring, and subsequently themixture was heated and stirred for 60 minutes. The mixture was adjustedto pH 5 by addition of 2-N hydrochloric acid, and the precipitatedcrystal was separated by filtration and subjected to through circulationdrying to give the title compound (1.90 g, 70%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 13.54 (brs, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.72 (d,J=2.3 Hz, 1H), 7.51 (dd, J=2.3, 8.5 Hz, 1H), 7.27 (s, 1H), 4.16 (s, 3H)

Mass, m/z: 270 (M⁺, base)

Example 8-2 5-(2,4-Dichlorophenyl)-1-methyl-1H-pyrazole-3-carboxylicacid

The compound 8-1-2-B was used and subjected to the same procedure as inthe Step 8-1-3 to give the title compound.

¹H-NMR (DMSO-d₆) δ: 12.75 (brs, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.61-7.55(m, 2H), 6.80 (s, 1H), 3.71 (s, 3H)

Mass, m/z: 270 (M⁺, base)

Examples 8-3 to 8-29 and 8-31 to 8-35

According to the production processes shown in the following table,compounds shown in the following table were used instead of2′,4′-dichloroacetophenone as a carbonyl compound or methylhydrazine asa ring-forming component to give the objective compounds.

TABLE 19 Ring- Pro- Carbonyl forming duction compound component processExample ¹H-NMR Mass, m/z Acetophenone — Example 8-1 Example 8-3  

(DMSO-d₆) δ: 13.41 (br s, 1H), 7.85-7.83 (m, 2H), 7.43-7.40 (m, 2H),7.34- 7.31 (m, 1H), 7.28(s, 1H), 4.13 (s, 3H) 202 (M⁺, base) 2′-Methylacetophenone — Example 8-1 Example 8-4  

(DMSO-d₆) δ: 13.39 (br s, 1H), 7.56-7.53 (m, 1H), 7.29-7.21 (m, 3H),7.05 (s, 1H), 4.13 (s, 3H), 2.44 (s, 3H) 216 (M⁺, base) — Ethylhydrazine Example 8-1 Example 8-5  

(DMSO-d₆) δ: 13.54 (br s, 1H), 7.85(d, J = 8.5 Hz, 1H), 7.72 (d, J = 2.3Hz, 1H), 7.51 (dd, J = 2.3, 8.5 Hz, 1H), 7.28 (s, 1H), 4.58 (q, J = 7.3Hz, 2H), 1.40 (t, J = 7.3 Hz, 3H) 284 (M⁺, base), 256 3′,4′- Dichloroacetophenone Ethyl hydrazine Example 8-1 Example 8-6  

(DMSO-d₆) δ: 13.51 (br s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.85 (dd, J =2.3, 8.5 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.43 (s, 1H), 4.55 (q, J =7.3 Hz, 2H), 1.39 (t, J = 7.3 Hz, 3H) 284 (M⁺, base) 2′-Methoxyacetophenone — Example 8-1 Example 8-7  

(DMSO-d₆) δ: 13.34 (br s, 1H), 7.88 (dd, J = 1.5, 7.7 Hz, 1H), 7.34(ddd, J = 1.5, 7.3, 8.9 Hz, 1H), 7.23 (s, 1H), 7.11 (d, J = 8.5 Hz, 1H),7.00 (dt, J = 0.8, 7.3 Hz, 1H), 4.13 (s, 3H), 3.88 (s, 3H) 232 (M⁺,base) 4′-Fluoro- 2′-methoxy acetophenone Ethyl hydrazine Example 8-1Example 8-8  

(DMSO-d₆) δ: 13.35 (br s, 1H), 7.90 (dd, J = 6.9, 8.5 Hz, 1H), 7.18 (s,1H), 7.03 (dd, J = 2.3, 11.6 Hz, 1H), 6.84 (dt, J = 2.7, 8.5 Hz, 1H),4.55 (q, J = 7.3 Hz, 2H), 3.90 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H) 264(M⁺, base) 4′-Chloro- 2′-methoxy acetophenone — Example 8-1 Example 8-9 

(DMSO-d₆) δ: 13.39 (br s, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.22 (s, 1H),7.20 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 1.9, 8.1 Hz, 1H), 4.13 (s, 3H),3.92 (s, 3H) 266 (M⁺, base)

TABLE 20 Ring- Pro- Carbonyl forming duction compound component processExample ¹H-NMR Mass, m/z 4′-Chloro- 2′-methoxy acetophenone Ethylhydrazine Example 8-1 Example 8-10  

(DMSO-d₆) δ: 13.41 (br s, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.22 (s, 1H),7.20 (d, J = 1.9 Hz, 1H), 7.07 (dd, J = 1.9, 8.5 Hz, 1H), 4.56 (q, J =7.3 Hz, 2H), 3.92 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H) 280 (M⁺, base)4′-Chloro- 2′-methoxy acetophenone Isopropyl hydrazine Example 8-1Example 8-11  

(DMSO-d₆) δ: 12.64 (br s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.28 (d, J =1.9 Hz, 1H), 7.14 (dd, J = 1.9, 8.1 Hz, 1H), 6.61 (s, 1H), 4.20-4.14 (m,1H), 3.82 (s, 3H), 1.32 (d, J = 6.9 Hz, 6H) 294 (M⁺, base) 2′-Methoxy-4′-methyl acetophenone Ethyl hydrazine Example 8-1 Example 8-12  

(DMSO-d₆) δ: 13.29 (br s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.18 (s, 1H),6.93 (s, 1H), 6.82 (d, J = 7.7 Hz, 1H), 4.55 (q, J = 6.9 Hz, 2H), 3.86(s, 3H), 1.37 (t, J = 6.9 Hz, 3H) 260 (M⁺, base) 2′,4′- Dimethoxyacetophenone — Example 8-1 Example 8-13  

(DMSO-d₆) δ: 13.28 (br s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.13 (s, 1H),6.65 (d, J = 2.3 Hz, 1H), 6.60 (dd, J = 2.3, 8.5 Hz, 1H), 4.11 (s, 3H),3.87 (s, 3H), 3.80 (s, 3H) 262 (M⁺, base) 3′,4′- Dimethoxy acetophenone— Example 8-1 Example 8-14  

(DMSO-d₆) δ: 13.36 (br s, 1H), 7.39-7.36 (m, 2H), 7.25 (s, 1H), 6.98 (d,J = 8.1 Hz, 1H), 4.11 (s, 3H), 3.82 (s, 3H), 3.78 (s, 3H) 262 (M⁺, base)2′,6′- Dimethoxy acetophenone — Example 8-1 Example 8-15  

(CDCl₃) δ: 7.30 (t, J = 8.1 Hz, 1H), 7.05 (s, 1H), 6.64 (s, 1H), 6.62(s, 1H), 4.26 (s, 3H), 3.78 (s, 6H) 262 (M⁺, base) 2′,4′- Dimethylacetophenone — Example 8-1 Example 8-16  

(DMSO-d₆) δ: 13.38 (br s, 1H), 7.45 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H)7.05 (d, J = 7.7 Hz, 1H), 7.01 (s, 1H), 4.12 (s, 3H), 2.40 (s, 3H), 2.29(s, 3H) 230 (M⁺, base)

TABLE 21 Ring- Pro- Carbonyl forming duction compound component processExample ¹H-NMR Mass, M/Z 2′,4′- Dimethyl acetophenone Ethyl hydrazineExample 8-1 Example 8-17  

(DMSO-d₆) δ: 13.38 (br s, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.09 (s, 1H),7.05 (d, J = 8.5 Hz, 1H), 7.00 (s, 1H), 4.55 (q, J = 7.3 Hz, 2H), 2.41(s, 3H), 2.29 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H) 244 (M⁺, base) 2′,4′-Dimethyl acetophenone Benzyl hydrazine Example 8-1 Example 8-18  

(DMSO-d₆) δ: 12.73 (br s, 1H), 7.29-7.21 m, 3H), 7.14 (s, 1H), 7.11-7.07(m, 2H), 6.90 (dd, J = 1.9, 7.7 Hz, 2H), 6.71 (s, 1H), 5.16 (s, 2H),2.32 (s, 3H), 1.95 (s, 3H) 306 (M⁺, base) 2′-Trifluoro methylacetophenone — Example 8-1 Example 8-19  

(DMSO-d₆) δ: 13.51 (br s, 1 H), 7.84 (d, J = 8.1 Hz, 1H), 7.75-7.72 (m,1H), 7.68 (d, J = 6.9 Hz, 1H), 7.64-7.60 (m, 1H), 6.96 (s, 1H), 4.14 (s,3H) 270 (M⁺, base) 4′-Dimethyl amino acetophenone — Example 8-1 Example8-20  

(DMSO-d₆) δ: 13.29 (br s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.09 (s, 1H),6.74 (d, J = 8.9 Hz, 1H), 4.09 (s, 3H), 2.92 (s, 6H) 245 (M⁺, base)4-Chromanone — Example 8-1 Example 8-21  

(DMSO-d₆) δ: 13.71 (br s, 1H), 7.24-7.20 (m, 1H), 7.02-6.98 (m, 1H),6.96- 6.92 (m, 1H), 5.44 (s, 2H), 4.12 (s, 3H) 230 (M⁺), 229 (base)4-Chromanone Ethyl hydrazine Example 8-1 Example 8-22  

(DMSO-d₆) δ: 13.71 (br s, 1H), 7.62 (dd, J = 1.5, 7.7 Hz, 1H), 7.22 (dt,J = 1.5, 7.7 Hz, 1H), 7.00 (t, J = 7.7 Hz, 1 H), 6.93 (d, J = 7.7 Hz,1H), 5.41 (s, 2H), 4.55 (q, J = 7.3 Hz, 2H), 1.37 (t, J = 7.3 Hz, 3H)244 (M⁺), 215 (base) 2-Acetylfuran — Example 8-1 Example 8-23  

(DMSO-d₆) δ: 13.49 (br s, 1H), 7.71 (dd, J = 0.8, 1.9 Hz, 1H), 7.03 (s,1H), 6.78 (d, J = 3.1 Hz, 1H), 6.57 (dd, J = 1.5, 3.1 Hz, 1H), 4.11 (s,3H) 192 (M⁺, base)

TABLE 22 Ring- Pro- Carbonyl forming duction compound component processExample ¹H-NMR Mass, m/z 1-(4-Chloro- 2-methoxy phenyl) propan-1-one —Example 8-1 Example 8-24  

(DMSO-d₆) δ: 13.34 (br s, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.18 (d, J =1.9 Hz, 1H), 7.07 (dd, J = 1.9, 8.1 Hz, 1H), 4.05 (s, 3H), 3.79 (s, 3H)280 (M⁺, base) Acetophenone — Example 8-2 Example 8-25  

(DMSO-d₆) δ: 12.66 (br s, 1H), 7.59-7.46 (m, 5H), 6.83 (s, 1H), 3.91 (s,3H) 202 (M⁺, base) 4′-Fluoro- 2′-methoxy acetophenone — Example 8-2Example 8-26  

(DMSO-d₆) δ: 12.60 (br s, 1H), 7.35 (dd, J = 6.9, 8.5 Hz, 1H), 7.11 (dd,J = 2.3, 11.6 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 3.83 (s, 3H),3.67 (s, 3H) 250 (M⁺, base) 4′-Chloro- 2′-methoxy acetophenone — Example8-2 Example 8-27  

(DMSO-d₆) δ: 12.65 (br s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.28 (d, J =1.9 Hz, 1H), 7.14 (dd, J = 1.9, 8.1 Hz, 1H), 6.69 (s, 1H), 3.84 (s, 3H),3.68 (s, 3H) 266 (M⁺, base) 2′,4′- Dimethyl acetophenone hydrazineExample 8-1 Example 8-28  

(DMSO-d₆) δ: 7.39 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J = 8.1Hz, 1H), 6.86 (s, 1H), 2.36 (s, 3H), 2.31 (s, 3H) 256 (M⁺, base)4′-Chloro- 2′-methoxy acetophenone Hydrazine monohydrate Example 8-1Example 8-29  

(DMSO-d₆) δ: 7.87 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 7.07(dd, J = 2.3, 8.5 Hz, 1H), 7.00 (s, 1H), 3.92 (s, 3H) 252 (M⁺, base)4′-Fluoro- 2′-methyl acetophenone — Example 8-1 Example 8-31  

(DMSO-d₆) δ: 13.41 (br s, 1H), 7.58 (dd, J = 6.2, 8.5 Hz, 1H), 7.15 (dd,J = 2.7, 10.4 Hz, 1H), 7.09-7.05 (m, 1H), 7.04 (s, 1H), 4.13 (s, 3H),2.45 (s, 3H) 234 (M⁺) (base), 189, 148 2′-methoxy acetophenone Ethylhydrazine Example 8-1 Example 8-32  

(DMSO-d₆) δ: 13.27 (br s, 1H), 7.90 (dd, J = 1.5, 7.7 Hz, 1H), 7.33(ddd, J = 1.9, 7.3, 8.5 Hz, 1H), 7.23 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H),7.00 (t, 1 H), 4.56 (q, J = 7.3 Hz, 2H), 3.88 (s, 3H), 1.38 (t, J = 7.3Hz, 3H) 246 (M⁺) (base), 217, 201, 171

TABLE 23 Ring- Pro- Carbonyl forming duction compound component processExample ¹H-NMR Mass, m/z 4′-Fluoro- 2′-methoxy acetophenone — Example8-1 Example 8-33  

(DMSO-d₆) δ: 13.36 (br s, 1H), 7.89 (dd, J = 6.9, 8.5 Hz, 1H), 7.18 (s,1H), 7.02 (dd, J = 2.3, 11.6 Hz, 1H), 6.83 (dt, J = 2.7, 8.5 Hz, 1H),4.12 (s, 3H), 3.90 (s, 3H) 250 (M⁺) (base), 220, 205, 175 2′-Methoxy-4′-methyl acetophenone — Example 8-1 Example 8-34  

(DMSO-d₆) δ: 13.30 (br s, 1H), 7.77 (d, J = 7.7 Hz, 1H) 7.19 (s, 1H)6.94 (s, 1H), 6.81 (d, J = 8.1 Hz, 1H), 4.11 (s, 3H), 3.87 (s, 3H), 2.34(s, 3H) 246 (M⁺) (base), 217, 201, 173 1-Indanone — Example 8-1 Example8-35  

(DMSO-d₆) δ: 12.66 (br s, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.58 (d, J =7.3 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 7.32 (t, J = 7.7 Hz, 1H) 4.16 (s,3H), 3.68 (s, 2H) 214 (M⁺) (base), 169, 140, 115

Example 8-30 2,5-Dimethyl-2H-pyrazole-3-carboxylic acid

The title compound was obtained according to the same procedure as inExample 8-1 except that ethyl 2,4-dioxopentanoate was used instead ofethyl 4-(2,4-dichlorophenyl)-2,4-dioxobutyrate.

¹H-NMR (DMSO-d₆) δ: 13.16 (brs, 1H), 6.58 (s, 1H), 3.98 (s, 3H), 2.16(s, 3H)

Mass, m/z: 140 (M⁺, base)

In the formulae, Ar represents a thiazole or pyrazole ring which mayhave a carbocyclic (homocyclic) or heterocyclic group as a substituent;R and R′ are the same or different and each represent a hydrogen atom, ahalogen atom, an alkyl group, a haloalkyl group, an alkoxy group, anamino group or an N-alkyl-substituted amino group; R″ represents acarbocyclic (homocyclic) or heterocyclic group which may have asubstituent (such as an alkyl group, a hydroxyl group, an alkoxy group,an alkoxyalkyl group, or an alkylthio group); and R′″ represents analkyl group.

Example 9-1 Step 9-1[2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamic acid1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethyl ester

In toluene (50 ml),2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (1.11 g,3.91 mmol) prepared in Example 7-1 and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol (870mg, 4.30 mmol) prepared in Example 3-1 were suspended. Triethylamine(475 mg, 4.69 mmol) and then diphenylphosphoryl azide (1.18 g, 4.30mmol) were added to the suspension, and the mixture was heated underreflux for 2 hours. Chloroform was added to the mixture, and theresulting mixture was washed with a saturated sodium bicarbonatesolution. The washed mixture was dried over anhydrous magnesium sulfateand then concentrated. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=10:1) to give the title compound(1.34 g, 71%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 10.08 (brs, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.62 (s,1H), 7.47 (d, J=8.1 Hz, 1H), 7.30 (d, J=1.9 Hz, 1H), 7.27 (d, J=7.7 Hz,1H), 7.12 (dd, J=1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.11-4.08 (m, 2H), 4.02(s, 3H), 2.98-2.95 (m, 2H), 2.31 (s, 3H), 2.07-2.04 (m, 2H), 1.97-1.92(m, 2H)

Mass, m/z: 482 (M⁺), 438, 280, 202 (base)

Examples 9-2 to 9-377

The objective compounds were obtained according to the same procedure asin Example 9-1 except that any one of carboxylic acids or any one ofhydroxy compounds shown in the following table were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid or(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol.

TABLE 24 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-8  4-Methoxy benzyl alcohol Example 9-2  

(DMSO-d₆) δ: 10.00 (br s, 1H), 7.41-7.37 (m, 2H), 7.25-7.19 (m, 2H),6.99-6.96 (m, 2H), 6.90-6.86 (m, 2H), 5.13 (s, 2H), 3.99 (s, 3H), 3.74(s, 3H), 2.30 (s, 3H) 384 (M⁺), 121 (base) Example 7-1  4-Methoxy benzylalcohol Example 9-3  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.39 (d, J =8.9 Hz, 2H), 7.30 (d, J = 1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H),6.96 (d, J = 8.9 Hz, 2H), 5.12 (s, 2H), 4.02 (s, 3H), 3.77 (s, 3H), 2.31(s, 3H) 418 (M⁺), 374, 121 (base) Example 7-20 4-Methoxy benzyl alcoholExample 9-4  

(DMSO-d₆) δ: 9.69 (br s, 1H), 7.36-7.32 (m, 2H), 6.95 (d, J = 8.9 Hz, 2H), 5.07 (s, 2H), 3.76 (s, 3H), 2.16 (s, 3H), 2.03 (s, 3H), 1.91 (d, J =2.7 Hz, 6H), 1.80-1.68 (m, 6H) 412 (M⁺), 368, 121 (base) Example 7-8 4-Methylthio benzyl alcohol Example 9-5  

(DMSO-d₆) δ: 10.03 (br s, 1H), 8.18 (dd, J = 1.5, 7.7 Hz, 1H), 7.42-7.37(m, 3H), 7.30 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 7.7 Hz, 1H), 7.08-7.04(m, 1H), 5.16 (s, 2H), 3.98 (s, 3H), 2.49 (s, 3 H), 2.31 (s, 3H) 400(M⁺), 137 (base) Example 7-8  2,3-Dihydro- 1-benzofuran- 5-ylmethanolExample 9-6  

(DMSO-d₆) δ: 9.97 (br s, 1H), 8.17 (dd, J = 1.5, 8.1 Hz, 1H), 7.41-7.37(m, 1H), 7.31 (s, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 8.1 Hz,1H), 7.08-7.04 (m, 1H), 6.77 (d, J = 8.1 Hz, 1H), 5.10 (s, 2H), 4.53 (t,J = 8.9 Hz, 2H), 3.98 (s, 3H), 3.18 (t, J = 8.5 Hz, 2H), 2.30 (s, 3H)396 (M⁺), 133 (base)

TABLE 25 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/z —2,3-Dihydro- 1-benzofuran- 5-ylmethanol Example 9-7  

(DMSO-d₆) δ: 10.04 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.32 (s, 1H),7.30 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 1.9,8.5 Hz, 1H), 6.77 (d, J = 8.9 , Hz 1H), 5.10 (s, 2H), 4.54 (t, J = 8.9Hz, 2H), 4.02 (s, 3H), 3.19 (t, J = 8.9 Hz, 2H), 2.31 (s, 3H) 386 (M⁺ −44), 133 (base) Example  7-16 2,3-Dihydro- 1-benzofuran- 5-ylmethanolExample 9-8  

(DMSO-d₆) δ: 10.07 (br s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H),7.17 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 6.77(d, J = 8.1 Hz, 1H), 5.10 (s, 2H), 4.54 (t, J = 8.9 Hz, 2H), 3.18 (t, J= 8.9 Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H) 394 (M⁺), 133(base) Example 7-8 3,4- Methylene- dioxy benzyl alcohol Example 9-9  

(DMSO-d₆) δ: 10.03 (br s, 1H), 8.17 (dd, J = 1.5, 7.7 Hz, 1H), 7.42-7.37 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08-7.02 (m, 1H), 6.94 (s, 1H),6.86-6.83 (m, 2H), 5.98 (s, 2H), 5.09 (s, 2H), 3.99 (s, 3H), 2.31 (s,3H) 398 (M⁺), 135 (base) Example 7-8 3-Dimethyl- amino benzyl alcoholExample 9-10  

(DMSO-d₆) δ: 10.02 (br s, 1H), 8.18 (dd, J = 1.5, 7.7 Hz, 1H), 7.41-7.37 (m, 1H), 7.22-7.17 (m, 2H), 7.08-7.04 (m, 1H), 6.78 (s, 1H),6.72-6.70 (m, 2H), 5.13 (s, 2H), 3.98 (s, 3H), 2.90 (s, 6H), 2.31 (s,3H) 397 (M⁺), 134 (base) — 3-Dimethyl- amino benzyl alcohol Example 9-11 

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.51-7.43 (m,1H), 7.36-7.32 (m, 2H), 7.22-7.18 (m, 1H), 6.72- 6.70 (m, 2H), 5.13 (s,2H), 4.01 (s, 3H), 2.90 (s, 6H), 2.32 (s, 3H) 431 (M⁺), 253, 134 (base)

TABLE 26 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-9  1-Methyl-1H- benzotriazole- 5-methanol Example 9-12  

(DMSO-d₆) δ: 10.23 (br s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H),7.67- 7.63 (m, 2H), 7.38-7.28 (m, 3H), 5.38 (s, 2H), 4.32 (s, 3H), 2.52(s, 3H), 2.33 (s, 3H) 393 (M⁺), 349, 118 (base) Example 7-8 1-Methyl-1H- benzotriazole- 5-methanol Example 9-13  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.18 (dd, J = 1.5, 7.7 Hz, 1H), 8.12 (s,1H), 7.89 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.41-7.37 (m,1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08-7.04 (m, 1H), 5.37 (s, 2H), 4.32 (s,3H), 3.90 (s, 3H), 2.32 (s, 3H) 409 (M⁺), 365, 118 (base) Example 7-131-Methyl-1H- benzotriazole- 5-methanol Example 9-14  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.19 (dd, J = 6.9, 8.5 Hz, 1H), 8.12 (s,1H), 7.89 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.37 (s, 2H), 4.32(s, 3H), 4.00 (s, 3H), 2.31 (s, 3H) 427 (M⁺), 383, 118 (base) —1-Methyl-1H- benzotriazole- 5-methanol Example 9-15  

(DMSO-d₆) δ:10.16 (br s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.12 (s, 1H),7.89 (d, J = 8.9 Hz, 1H) , 7.64 (d, J = 8.5 Hz, 1H) , 7.30 (d, J =1.9Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.37 (s, 2H), 4.32 (s, 3H),4.01 (s, 3H), 2.32 (s, 3H) 443 (M⁺), 399, 280, 118 (base) Example 7-141-Methyl-1H- benzotriazole- 5-methanol Example 9-16  

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.12 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H),7.89 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.88(d, J = 7.3 Hz, 1H), 5.36 (s, 2H), 4.32 (s, 3H), 3.96 (s, 3H), 2.36 (s,3H), 2.30 (s, 3H) 423 (M⁺), 379, 118 (base)

TABLE 27 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample  7-16 1-Methyl-1H- benzotriazole- 5-methanol Example 9-17  

(DMSO-d₆) δ: 10.17 (br s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.9 Hz, 1H),7.64 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.14 (3, 1H), 7.10(d, J = 8.1 Hz, 1H), 5.37 (s, 2H), 4.32 (s, 3H), 2.50 (s, 3H), 2.31 (s,6H) 407 (M⁺), 363, 118 (base) Example 7-5 1-Methyl-1H- benzotriazole-5-methanol Example 9-18  

(DMSO-d₆) δ: 10.38 (br s, 1H), 8.19-8.17 (m, 1H), 8.14 (d, J = 8.9 Hz,1H), 7.89 (d, J = 8.5 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.60 (dd, J =2.7, 8.9 Hz, 1H), 7.35 (dt, J = 2.7, 8.9 Hz, 1H), 5.38 (s, 2H), 4.32 (s,3H), 2.35 (s, 3H) 431 (M⁺), 387, 118 (base) Example 7-6 1-Methyl-1H-benzotriazole- 5-methanol Example 9-19  

(DMSO-d₆) δ: 10.24 (br s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H),7.70 (dd, J = 6.2, 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.21 (dd, J =2.7, 10.2 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H), 5.38 (s, 2H), 4.32(s, 3H), 2.53 (s, 3H), 2.32 (s, 3H) 411 (M⁺), 367, 248 (base) Example7-7 1-Methyl-1H- benzotriazole- 5-methanol Example 9-20  

(DMSO-d₆) δ: 10.30 (br s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.5 Hz, 1H),7.70 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.9 Hz,1H), 7.35(dd, J = 2.3, 8.5 Hz, 1H), 5.38 (s, 2H), 4.32 (s, 3H), 2.53 (s,3H), 2.34 (s, 3H) 427 (M⁺), 383, 118 (base) Example  7-17 1-Methyl-1H-benzotriazole- 5-methanol Example 9-21  

(DMSO-d₆) δ: 10.16 (br s, 1H), 8.12 (s, 1H), 7.89 (d, J = 8.1 Hz, 1H),7.84 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 5.8 Hz,1H), 6.94-6.91 (m, 1H), 5.37 (s, 2H), 4.74 (t, J = 8.5 Hz, 2H), 4.32 (s,3H), 3.28 (t, J = 8.5 Hz, 2H), 2.32 (s, 3H) 421 (M⁺), 377, 258 (base)

TABLE 28 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-8  Example 5-1 Example 9-22  

(DMSO-d₆) δ: 10.07 (br s, 1H), 8.18 (dd, J = 1.5, 7.7 Hz, 1H), 8.13 (s,1H), 7.94 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.41- 7.37 (m,1H), 7.20 (d, J = 8.5 Hz, 1H), 7.08-7.04 (m, 1H), 5.37 (s, 2H), 4.75 (q,J = 7.3 Hz, 2H), 3.98 (s, 3H), 2.32 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H)423 (M⁺), 379, 104 (base) Example 7-13 Example 5-1 Example 9-23  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.19 (dd, J = 6.9, 8.5 Hz, 1H), 8.13 (s,1H), 7.94 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.37 (s, 2H), 4.65(q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 2.31 (s, 3H), 1.52 (t, J = 7.3 Hz,3H) 441 (M⁺), 397, 104 (base) — Example 5-1 Example 9-24  

(DMSO-d₆) δ: 10.15 (br s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.13 (s,1H),7.94 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 1.9Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.37 (s, 2H), 4.7 5 (q, J = 7.3Hz, 2H), 4.01 (s, 3H), 2.32 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) 457 (M⁺),413, 104 (base) Example 7-14 Example 5-1 Example 9-25  

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.12 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H),7.94 (d, J = 8.5 Hz, 1H), 7. 63 (d, J = 8.5 Hz, 1H), 7.02 (s, 1H), 6.88(d, J = 8.5 Hz, 1H) 5.36 (s, 2H), 4.75 (q, J = 7.3 Hz, 2H), 3.96 (s,3H), 2.35 (s, 3H), 2.30 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) 437 (M⁺), 393,104 (base) Example 7-16 Example 5-1 Example 9-26  

(DMSO-d₆) δ: 10.16 (br s, 1H), 8.12 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H),7.63 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.10(d, J = 8.1 Hz, 1H), 5.37 (s, 2H), 4.75 (q, J = 7.3 Hz, 2H), 2.50 (s,3H), 2.31 (s, 3H), 2.31 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) 421 (M⁺), 377,104 (base)

TABLE 29 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-6 Example 5-1 Example 9-27  

(DMSO-d₆) δ: 10.24 (br s, 1H), 8.13 (s, 1H), 7.94 (d, J = 8.5 Hz, 1H),7.72-7.68 (m, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.23-7.20 (m, 1H), 7.12(dt, J = 2.7, 8.5 Hz, 1H), 5.37 (s, 2H), 4.75 (q, J = 7.3 Hz, 2H), 4.32(s, 3H), 2.52 (s, 3H), 2.33 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) 425 (M⁺),381, 104 (base) Example 7-7 Example 5-1 Example 9-28  

(DMSO-d₆) δ: 10.30 (br s, 1H), 8.13 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H),7.70 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.9 Hz,1H), 7.35 (dd, J = 1.9, 8.5 Hz, 1H), 5.38 (s, 2H), 4.75 (q, J = 7.3 Hz,2H), 2.53 (s, 3H), 2.34 (s, 3H), 1.52 (t, J = 7.3 Hz, 3H) 441 (M⁺), 397,104 (base) Example 7-8 (1-Methyl- 1H-indol-5- yl)methanol Example 9-29  

(DMSO-d₆) δ: 9.98 (br s, 1H), 8.17 (dd, J = 1.5, 8.1 Hz, 1H), 7.64 (s,1H), 7.46 (d, J = 8.5 Hz, 1H), 7.41- 7.35 (m, 2H), 7.24 (d, J = 8.5 Hz,1H), 7.19 (d, J = 8.1 Hz, 1H), 7.07-7.04 (m, 1H), 6.45 (d, J = 2.7 Hz,1H), 5.27 (s, 2H), 3.98 (s, 3H), 3.80 (s, 3H), 2.30 (s, 3H) 407 (M⁺),363, 144 (base) — (1-Methyl- 1H-indol-5- yl)methanol Example 9-30  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H),7.46 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 3.1 Hz, 2H), 7.30 (d, J = 1.9 Hz,1H), 7.24 (d, J = 8.5 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 6.45 (d,J = 2.7 Hz, 1H), 5.27 (s, 2H), 4.02 (s, 3H), 3.80 (s, 3H), 2.30 (s, 3H)397 (M⁺ − 44), 254, 144 (base) Example 7-7 (1-Methyl- 1H-indol-5-yl)methanol Example 9-31  

(DMSO-d₆) δ: 10.21 (br s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.64 (s, 1H),7.46 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.37-7.33 (m, 2H),7.24 (dd, J = 1.5, 8.5 Hz, 1H), 6.45 (d, J = 3.1 Hz, 1H), 5.28 (s, 2H),3.80 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H) 381 (M⁺ − 44), 144 (base)

TABLE 30 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/z4-Methyl-2- phenyl- 1,3-thiazole- 5-carboxylic acid Example 1-1 Example9-32  

(DMSO-d₆) δ: 10.20 (br s, 1H), 8.21 (s, 1H), 7.84 (d, J = 1.5 Hz, 1H),7.82 (d, J = 1.2 Hz, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.78-7.36 (m, 4H), 5.32 (s, 2H), 3.85 (s, 3H), 2.31 (s, 3H) 334 (M⁺ − 44),145 (base) Example 7-9  Example 1-1 Example 9-33  

(DMSO-d₆) δ: 10.16 (br s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.66 (d, J =6.9 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.33-7.26 (m, 3H), 5.32 (s, 2H), 3.85 (s, 3H), 2.52 (s, 3H), 2.32 (s, 3H) 392(M⁺), 348, 145 (base) Example 7-10 Example 1-1 Example 9-34  

(DMSO-d₆) δ: 10.18 (br s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.66 (s, 1H),7.62- 7.58 (m, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H),7.23 (d, J = 7.3 Hz, 1H), 5.32 (s, 2H), 3.85 (s, 3H), 2.36 (s, 3H), 2.30(s, 3H) 392 (M⁺), 145 (base) Example 7-11 Example 1-1 Example 9-35  

(DMSO-d₆) δ: 10.14 (br s, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.71 (d, J =7.1 Hz, 2H), 7.60 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.26(d, J = 8.1 Hz, 2H), 5.31 (s, 2H), 3.85 (s, 3H), 2.34 (s, 3H), 2.29 (s,3H) 392 (M⁺), 348, 145 (base) Example 7-12 Example 1-1 Example 9-36  

(DMSO-d₆) δ: 10.16 (br s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.39-7.34 (m, 3H), 7.30-7.26 (m,1H), 5.32 (s, 2H), 3.85 (s, 3H), 2.91 (q, J = 7.3 Hz, 2H), 2.31 (s, 3H),1.13 (t, J = 7.3 Hz, 3H) 406 (M⁺), 362, 145 (base)

TABLE 31 Hydroxy Carboxylic com- Mass, acid pound Example ¹H-NMR m/zExample 7-8  Example 1-1

(DMSO-d₆) δ: 10.02 (br s, 1H), 8.21 (d, J = 2.3 Hz, 1H), 8.18 (dd, J =1.5, 7.7 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H),7.41-7.36 (m, 2H), 7.20 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m, 1H), 5.31 (s,2H), 3 98 (s, 3H), 3.85 (s, 3H), 2.31 (s, 3H) 408 (M⁺),  364,  246, 145(base) Example 7-13 Example 1-1

(DMSO-d₆) δ: 10.03 (br s, 1H), 8.21 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H),7.75 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.13(dd, J = 2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.31 (s,2H), 4.00 (s, 3H), 3.85 (s, 3H), 2.30 (s, 3H) 426 (M⁺),  382, 145 (base)— Example 1-1

(DMSO-d₆) δ: 10.10 (br s, 1H), 8.21 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.40-7.35 (m, 1H), 7.30 (d, J =1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H), 4.02 (s, 3H),3.85 (s, 3H), 2.31 (s, 3H) 442 (M⁺),  398,  280, 133 (base) Example 7-14Example 1-1

(DMSO-d₆) δ: 9.94 (br s, 1H), 8.21 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H),7.74 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.02(s, 1H), 6.87 (dd, J = 0.8, 8.1 Hz, 1H), 5.30 (s, 2H), 3.96 (s, 3H),3.85 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H) 422 (M⁺)  378, 145 (base)

TABLE 32 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-15 Example 1-1

(DMSO-d₆) δ: 9.87 (br s, 1H), 8.21 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H),7.74 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.73(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.9 Hz, 1H), 5.29 (s, 2H), 3.97(s, 3H), 3.85 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H) 438 (M⁺)  394, 133(base) Example 7-16 Example 1-1

(DMSO-d₆) δ: 10.11 (br s, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.59 (d, J =8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.14(s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.31 (s, 2H), 3.85 (s, 3H), 2.31 (s,9H) 406 (M⁺)  362,  244, 145 (base) Example 7-2  Example 1-1

(DMSO-d₆) δ: 10.33 (br s, 1H), 8.21 (s, 1H), 8.14 (dt, J = 1.6, 7.8 Hz,1H), 7.76 (s, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.49-7.43 (m, 1H),7.40-7.30 (m, 2H), 5.33 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H) 396 (M⁺), 352,  234, 145 (base) Example 7-3  Example 1-1

(DMSO-d₆) δ: 10.32 (br s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.67-7.63 (m,1H), 7.62- 7.59 (m, 2H), 7.53-7.49 (m, 1H), 7.38-7.36 (m, 1H), 7.25 (dt,J = 2.3, 8.5 Hz, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 2.32 (s, 3H) 396 (M⁺) 352,  234, 145 (base) Example 7-4  Example 1-1

(DMSO-d₆) δ: 10.22 (br s, 1H), 8.22 (s, 1H), 7.89 (dd, J = 3.1, 5.4 Hz,1H), 7.86 (dd, J = 3.1, 5.4 Hz, 1H), 7.75 (s, 1H), 7.59 (d, J = 8.1 Hz,1H), 7.37 (d, J = 8.5 Hz, 1H), 7.32-7.20 (m, 2H), 5.32 (s, 2H), 3.84 (s,3H), 2.30 (s, 3H) 396 (M⁺),  352,  234, 145 (base)

TABLE 33 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-38 Example 1-1

(DMSO-d₆) δ: 10.34 (br s, 1H), 8.21 (s, 1H), 8.20-8.14 (m, 1H), 7.75 (s,1H), 7.59 (d, J = 8.1 Hz, 1H), 7.48- 7.42 (m, 1H), 7.37 (d, J = 8.1 Hz,1H), 7.25-7.20 (m, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H) 414(M⁺),  370, 145 (base) Example 7-5  Example 1-1

(DMSO-d₆) δ: 10.33 (br s, 1H), 8.22 (s, 1H), 8.17 (dd, J = 6.2, 8.9 Hz,1H), 7.75 (s, 1H), 7.62-7.59 (m, 2H), 7.39-7.33 (m, 2H), 5.33 (s, 2H),3.85 (s, 3H), 2.34 (s, 3H) 386 (M⁺ −    44), 145 (base) Example 7-6 Example 1-1

(DMSO-d₆) δ: 10.19 (br s, 1H), 8.22 (s, 1H), 7.75 (s, 1H), 7.71-7.68 (m,1H), 7.60 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.21 (dd, J =2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H), 5.32 (s, 2H), 3.85(s, 3H), 2.52 (s, 3H), 2.31 (s, 3H) 410 (M⁺),  366, 145 (base) Example7-7  Example 1-1

(DMSO-d₆) δ: 10.25 (br s, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.38-7.34 (m, 2H), 5.32 (s, 2H), 3.85 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H) 382(M⁺ −    44),  145, 133 (base) Example 7-18 Example 1-1

(DMSO-d₆) δ: 8.22 (s, 1H), 7.74-7.73 (m, 1H), 7.71-7.66 (m, 1H), 7.61-7.56 (m, 2H), 7.37 (d, J = 8.5 Hz, 1H), 6.82 (dd, J = 3.5, 8.5 Hz, 1H),5.30 (s, 2H), 4.58 (t, J = 8.5 Hz, 2H), 3.85 (s, 3H), 3.23 (t, J = 8.5Hz, 2H), 2.26 (s, 3H) 420 (M⁺),  376, 258 (base)

TABLE 34 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/z4-Methyl- 2-[4- (trifluoro- methyl) phenyl] thiazole- 5- carboxylic acidExample 1-1

(DMSO-d₆) δ: 10.42 (br s, 1H), 8.21 (s, 1H), 8.04 (d, J = 8.5 Hz, 2H),7.80 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.38(dd, J = 1.5, 8.5 Hz, 1H), 5.34 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H) 446(M⁺)  402, 145 (base) Example 7-20 Example 1-1

(DMSO-d₆) δ: 9.71 (br s, 1H), 8.21 (s, 1H), 7.71 (s, 1H), 7.58 (d, J =8.5 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 5.26 (s, 2H), 3.84 (s, 3H), 2.17(s, 3H), 2.04 (s, 3H), 1.92 (d, J = 2.7 Hz, 6H), 1.78-1.65 (m, 6H) 436(M+),  392, 145 (base) Example 7-9  Example 1-2

(DMSO-d₆) δ: 10.16 (br s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.68-7.63 (m,2H), 7.36-7.27 (m, 4H), 5.31 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 2.52 (s,3H), 2.32 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 406 (M+),  362, 159 (base)Example 7-10 Example 1-2

(DMSO-d₆) δ: 10.18 (br s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.66-7.60 (m,3H), 7.36-7.31 (m, 2H), 7.23 (d, J = 7.3 Hz, 1H), 5.31 (s, 2H), 4.29 (q,J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H)406 (M⁺)  362, 159 (base) Example 7-11 Example 1-2

(DMSO-d₆) δ: 10.14 (br s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.71 (d, J =8.1 Hz, 2H), 7.64 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.26(d, J = 7.7 Hz, 2H), 5.31 (s, 2H), 4.29 (q, J = 7.3 Hz, 3H), 2.34 (s,3H), 2.29 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 406 (M+),  362, 159 (base)

TABLE 35 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-12 Example 1-2

(DMSO-d6) δ: 10.16 (br s, 1H), 8.27(s, 1H), 7.75 (s, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.39-7.34 (m, 3H), 7.30-7.26 (m,1H), 5.31 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 2.91 (q, J = 7.3 Hz, 2H),2.32 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H) 420(M⁺),  376, 159 (base) Example 7-8  Example 1-2

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.28 (s, 1H), 8.18 (dd, J = 1.5, 7.7 Hz,1H), 7.75 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.41-7.35 (m, 2H), 7.0 (d,J = 7.7 Hz, 1H), 7.06 (dt, J = 0.8, 7.7 Hz, 1H), 5.31 (s, 2H), 4.29 (q,J = 7.3 Hz, 2H), 4.03 (s, 3H), 2.31 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H)422 (M⁺),  378,  246, 159 (base) Example 7-13 Example 1-2

(DMSO-d₆) δ: 10.05 (br s, 1H), 8.28 (s, 1H), 8.18 (dd, J = 6.9, 8.9 Hz,1H), 7.75 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H),7.13 (dd, J = 2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.30(s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 2.30 (s, 3H), 1.41 (t,J = 7.3 Hz, 3H) 440 (M⁺),  396, 264 (base) — Example 1-2

(DMSO-d₆) δ: 10.10 (br s, 1H), 8.33 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),7.76 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.30(d, J = 2.3 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H), 4.30(q, J = 7.3 Hz, 2H), 4.02 (s, 3H), 2.31 (s, 3H), 1.42 (dt, J = 2.7, 7.3Hz, 3H) 456 (M⁺)  412, 147 (base) Example 7-14 Example 1-2

(DMSO-d₆) δ: 9.94 (br s, 1H), 8.27 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H),7.74 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.02(s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.30 (s, 2H), 4.29 (q, J = 7.3 Hz,2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H)436 (M⁺),  392, 131 (base)

TABLE 36 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-15 Example 1-2

(DMSO-d₆) δ: 9.87 (br s, 1H), 8.28 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H),7.74 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.72(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.5 Hz, 1H), 5.29 (s, 2H), 4.28(q, J = 7.3 Hz, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H), 1.42 (t,J = 7.3 Hz, 3H) 408 (M⁺ −    44), 147 (base) Example 7-16 Example 1-2

(DMSO-d₆) δ: 10.10 (br s, 1H), 8.28(s, 1H), 7.74 (s, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.14(s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.31 (s, 2H), 4.29 (q, J = 7.3 Hz,2H), 2.31 (s, 9H), 1.42 (t, J = 7.3 Hz, 3H) 376 (M⁺ −    44), 244 (base)Example 7-6  Example 1-2

(DMSO-d₆) δ: 10.21 (br s, 1H), 8.28 (s, 1H), 7.75 (s, 1H), 7.70 (dd, J =5.8, 8.5 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H),7.21 (dd, J = 2.7, 10.0 Hz, 1H), 7.13 (dt, J = 2.7, 8.5 Hz, 1H), 5.31(s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H), 1.41 (t,J = 7.3 Hz, 3H) 380 (M⁺ −    44),  248, 159 (base) Example 7-7  Example1-2

(DMSO-d₆) δ: 10.23 (br s, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.36(d, J = 1.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 5.31 (s, 2H), 4.29 (q, J= 7.3 Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H) 382(M⁺ −    44),  145, 133 (base) 4-Methyl- 2-[4- (trifluoro- methyl)phenyl] thiazole- 5- carboxylic acid Example 1-2

(DMSO-d₆) δ: 10.42 (br s, 1H), 8.28 (s, 1H), 8.04 (d, J = 8.1 Hz, 2H),7.80 (d, J = 8.5 Hz, 2H), 7.76 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.36(dd, J = 1.2, 8.1 Hz, 1H), 5.34 (s, 2H), 4.29 (q, J = 7.3 Hz, H), 2.35(s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 460 (M⁺)  416, 159 (base)

TABLE 37 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-8  Example 1-3

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.17 (dd, J = 1.5, 7.7 Hz, 1H), 7.75 (s,1H), 7.64 (d, J = 8.1 Hz, 1H), 7.41- 7.34 (m, 2H), 7.20 (d, J = 8.1 Hz,1H), 7.08-7.04 (m, 1H), 5.31 (s, 2H), 4.22 (t, J = 6.9 Hz, 2H), 3.98 (s,3H), 2.31 (s, 3H), 1.86-1.77 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H) 436 (M⁺) 392,  246, 161 (base) — Example 1-3

(DMSO-d₆) δ: 10.09 (br s, 1H), 8.26 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H), 7.30(d, J = 1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H), 4.22(t, J = 7.3 Hz, 2H), 4.02 (s, 3H), 2.31 (s, 3H), 1.84-1.79 (m, 2H), 0.84(t, J = 7.3 Hz, 3H) 470 (M⁺)  426, 280 (base) Example 7-14 Example 1-3

(DMSO-d₆) δ: 9.94 (br s, 1H), 8.26 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H),7.74 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.02(s, 1H), 6.87 (dd, J = 0.8, 8.1 Hz, 1H), 5.30 (s, 2H), 4.22 (t, J = 6.9Hz, 2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 1.86- 1.77 (m, 2H),1.84 (t, J = 7.3 Hz, 3H) 450 (M⁺),  406, 260 (base) Example 7-16 Example1-3

(DMSO-d₆) δ: 10.11 (br s, 1H), 8.26 (s, 1H), 7.74 (s, 1H), 7.64 (d, J =8.1 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.14(s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H), 4.22 (t, J = 6.9 Hz,2H), 2.50 (s, 3H), 2.31 (s, 6H), 1.86-1.77 (m, 2H), 0.84 (t, J = 7.3 Hz,3H) 434 (M⁺)  390, 173 (base) Example 7-13 Example 1-4

(DMSO-d₆) δ: 10.02 (br s, 1H), 8.36 (s, 1H), 8.18 (dd, J = 6.9, 8.9 Hz,1H), 7.74 (s, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H),7.13 (dd, J = 2.3, 11.2 Hz, 1H), 6.95-6.88 (m, 1H), 5.30 (s, 2H),4.80-4.73 (m, 1H), 4.00 (s, 3H), 2.30 (s, 3 H), 1.54 (d, J = 6.9 Hz, 6H)454 (M⁺)  410, 118 (base)

TABLE 38 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/z —Example 1-4

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.35 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.29(d, J = 1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H),4.80-4.52 (m, 1H), 4.01 (s, 3H), 2.31 (s, 3H), 1.54 (d, J = 6.6 Hz, 6H)470 (M⁺) 280 (base) Example 7-15 Example 1-4

(DMSO-d₆) δ: 9.87 (br s, 1H), 8.35 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H),7.74 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 6.72(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.9 Hz, 1H), 5.29 (s, 2H),4.80-4.73 (m, 1H), 3.96 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H), 1.54 (d, J= 6.6 Hz, 6H) 466 (M⁺),  422, 276 (base) Example 7-16 Example 1-4

(DMSO-d₆) δ: 10.12 (br s, 1H), 8.36 (s, 1H), 7.74 (s, 1H), 7.66 (d, J =8.5 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.14(s, 1H), 7.09 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H), 4.80-4.73 (m, 1H), 2.50(s, 3H), 2.31 (s, 6H), 1.84 (d, J = 6.3 Hz, 6H) 390 (M⁺ −    44), 244(base) Example 7-8  Example 2-1

(DMSO-d₆) δ: 10.00 (br s, 1H), 8.17 (dd, J = 1.9, 8.1 Hz, 1H), 7.61 (s,1H), 7.49 (d, J = 8.1 Hz, 1H), 7.39 (ddd, J = 1.5, 7.3, 8.5 Hz, 1H),7.28 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.06 (dt, J = 1.2,8.1 Hz, 1H), 5.28 (s, 2H), 4.03 (s, 3H), 3.74 (s, 3H), 2.53 (s, 3H),2.30 (s, 3H) 442 (M⁺),  378, 147 (base) Example 7-13 Example 2-1

(DMSO-d₆) δ: 10.02 (br s, 1H), 8.18 (dd, J = 6.9, 8.9 Hz, 1H), 7.61 (s,1H), 7.50 (d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.28 (s, 2H), 4.00(s, 3H), 3.74 (s, 3H), 2.54 (s, 3H), 2.30 (s, 3H) 440 (M⁺),  396, 159(base)

TABLE 39 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/z —Example 2-1

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.49 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 8.9 Hz,1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.28 (s, 2H), 4.02 (s, 3H), 3.73(s, 3H), 2.53 (s, 3H), 2.31 (s, 3H) 412 (M⁺ −    44) 159 (base) Example7-14 Example 2-1

(DMSO-d₆) δ: 9.93 (br s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H),7.49 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.02 (s, 1H), 6.87(d, J = 8.1 Hz, 1H), 5.27 (s, 2H), 3.96 (s, 3H), 3.74 (s, 3H), 2.53 (s,3H), 2.35 (s, 3H), 2.28 (s, 3H) 436 (M⁺),  392, 159 (base) Example 7-16Example 2-1

(DMSO-d₆) δ: 10.10 (br s, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H),7.49 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 2.53 (s, 3H), 2.50 (s,3H), 2.31 (s, 3H), 2.30 (s, 3H) 420 (M⁺),  376, 159 (base) Example 7-5 Example 2-1

(DMSO-d₆) δ: 10.31 (br s, 1H), 8.17 (dd, J = 6.2, 8.9 Hz, 1H), 7.61 (d,J = 2.3 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 7.35 (ddd, J = 2.7, 8.1, 8.9Hz, 1H), 7.28 (dd, J = 1.2, 8.5 Hz, 1H), 5.30 (s, 2H), 3.73 (s, 3H),2.53 (s, 3H), 2.33 (s, 3H) 400 (M⁺ −    44), 159 (base) Example 7-6 Example 2-1

(DMSO-d₆) δ: 10.17 (br s, 1H), 7.69 (dd, J = 6.2, 8.5 Hz, 1H), 7.61 (s,1H), 7.49 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.21 (dd, J =2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H), 5.29 (s, 2H), 3.74(s, 3H), 2.53 (s, 3H), 2.50 (s, 3H), 2.31 (s, 3H) 380 (M⁺ −    44), 159(base)

TABLE 40 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-7  Example 2-1

(DMSO-d₆) δ: 10.23 (br s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.50 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 2.3,8.5 Hz, 1H), 7.28 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 3.74 (s, 3H),2.53 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H) 396 (M⁺ −    44), 159 (base) —Example 2-2

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H),7.50 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 1.2 Hz,1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.02 (s, 3H), 3.74(s, 3H), 2.89 (q, J = 7.7 Hz, 2H), 2.31 (s, 3H), 1.33 (t, J = 7.7 Hz,3H) 426 (M⁺ −    44), 173 (base) Example 7-16 Example 2-2

(DMSO-d₆) δ: 10.09 (br s, 1H), 7.63 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.50 (d, J = 8.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3H), 2.88 (q, J = 7.3 Hz,2H), 2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.33 (t, J = 7.3 Hz, 3H)390 (M⁺ −    44), 244 (base) Example 7-12 Example 2-3

(DMSO-d₆) δ: 10.15 (br s, 1H), 7.61 (s, 1H), 7.54-7.51 (m, 2H),7.39-7.33 (m, 2H), 7.30-7.26 (m, 2H), 5.28 (s, 2H), 4.22 (q, J = 7.2 Hz,2H), 2.90 (q, J = 7.2 Hz, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 1.29 (t, J =7.2 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H) 434 (M⁺),  390, 173 (base) Example7-8  Example 2-3

(DMSO-d₆) δ: 9.99 (br s, 1H), 8.17 (dd, J = 1.5, 7.7 Hz, 1H), 7.61 (s,1H), 7.52 (d, J = 8.5 Hz, 1H), 7.41- 7.37 (m, 1H), 7.27 (d, J = 8.5 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.07-7.03 (m, 1H), 5.28 (s, 2H), 4.22 (q,J = 7.3 Hz, 2H), 3.98 (s, 3H), 2.54 (s, 3H), 2.30 (s, 3H), 1.29 (t, J =7.3 Hz, 3H) 392 (M⁺ −    44),  85 (base)

TABLE 41 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/z —Example 2-3

(DMSO-d₆) δ: 10.07 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H)7.52 (d, J = 8.5 Hz, 1H), 7.30-7.26 (m, 2H), 7.12 (dd, J = 1.9, 8.5 Hz,1H), 5.28 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 4.02 (s, 3H), 2.54 (s, 3H),2.31 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H) 426 (M⁺ −    44), 280 (base)Example 7-14 Example 2-3

(DMSO-d₆) δ: 9.92 (br s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H)7.52 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H) 6.87(d, J = 8.1 Hz, 1H), 5.27 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 3.96 (s,3H), 2.54 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H)466 (M⁺ −    44),  260, 161 (base) Example 7-16 Example 2-3

(DMSO-d₆) δ: 10.09 (br s, 1H), 7.61 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.52 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.5 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 2.54 (s,3H), 2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H)390 (M⁺ −    44), 173 (base) Example 7-7  Example 2-3

(DMSO-d₆) δ: 10.22 (br s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.52 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 2.3,8.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 4.22 (q, J = 6.9Hz, 2H), 2.54 (s, 3H), 2.31 (s, 3H), 1.29 (t, J = 6.9 Hz, 3H) 410 (M⁺ −   44), 173 (base) Example 7-12 Example 3-6

(DMSO-d₆) δ: 10.17 (br s, 1H), 7.69 (s, 1H), 7.57-7.52 (m, 2H),7.39-7.29 (m, 3H), 7.28-7.25 (m, 1H), 5.31 (s, 2H), 4.96 (s, 2H), 4.22-4.20 (m, 2H), 4.18-4.15 (m, 2H), 2.90 (q, J = 7.3 Hz, 2H), 2.31 (s, 3H),1.18 (t, J = 7.3 Hz, 3H) 448 (M⁺),  404, 287 (base)

TABLE 42 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-8  Example 3-6

(DMSO-d₆) δ: 10.02 (br s, 1H), 8.18 (dd, J = 1.9, 8.1 Hz, 1H), 7.69 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.34 (d, J = 7.7 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m, 1H), 5.31 (s, 2H), 4.96 (s,2H), 4.22-4.15 (m, 4H), 3.98 (s, 3H), 2.31 (s, 3H) 450 (M⁺),  406, 175(base) Example 7-13 Example 3-6

(DMSO-d₆) δ: 10.03 (br s, 1H), 8.18 (dd, J = 6.9, 8.5 Hz, 1H), 7.69 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.7, 8.5 Hz, 1H), 5.30 (s, 2H), 4.96(s, 2H), 4.21-4.17 (m, 4H), 4.00 (s, 3H), 2.3 (s, 3H)  264,  204,  85(base) — Example 3-6

(DMSO-d₆) δ: 10.10 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.9 Hz, H), 7.30 (d, J = 1.9 Hz,1H), 7.12 (dd, J = 2.3, 8.5 Hz, 1H), 5.31 (s, 2H), 4.96 (s, 2H),4.22-4.16 (m, 4H), 4.02 (s, 3H), 2.31 (s, 3H) 440 (M⁺ −    44),  85(base) Example 7-14 Example 3-6

(DMSO-d₆) δ: 9.95 (br s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 7.3 Hz, 1H), 7.02 (s, 1H), 6.87(dd, J = 0.8, 8.1 Hz, 1H), 5.30 (s, 2H), 4.96 (s, 2H), 4.21-4.17 (m,4H), 3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H) 464 (M⁺), 260 (base)Example 7-15 Example 3-6

(DMSO-d₆) δ: 9.88 (br s, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.68 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 2.3 Hz,1H), 6.66 (dd, J = 2.3, 8.9 Hz, 1H), 5.29 (s, 2H), 4.96 (s, 2H),4.22-4.16 (m, 4H), 3.97 (s, 3H), 3.83 (s, 3H), 2.2 (s, 3H) 480 (M⁺), 436, 276 (base)

TABLE 43 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-16 Example 3-6

(DMSO-d₆) δ: 10.11 (br s, 1H), 7.69 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H),7.55 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 7.7 Hz, 1H), 5.30 (s, 2H), 4.96 (s, 2H), 4.22-4.15 (m, 4H), 2.50(s, 3H), 2.31 (s, 6H) 448 (M⁺) 404, 187 (base) Example 7-6  Example 3-6

(DMSO-d₆) δ: 10.19 (br s, 1H), 7.71-7.68 (m, 2H), 7.55 (d, J = 8.5 Hz,1H), 7.33 (d, J = 7.7 Hz, 1H), 7.21 (dd, J = 2.3, 10.0 Hz, 1H), 7.12(dt, J = 2.7, 8.5 Hz, 1H), 5.31 (s, 2H), 4.96 (s, 2H), 4.22-4.15 (m,4H), 2.52 (s, 3H), 2.31 (s, 3H) 452 (M⁺) 406, 187 (base) Example 7-7 Example 3-6

(DMSO-d₆) δ: 10.25 (br s, 1H), 7.71-7.69 (m, 2H), 7.56 (d, J = 8.1 Hz,1H), 7.44 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 1.9 Hz, 1H), 7.34 (d, J =1.9 Hz, 1H), 5.32 (s, 2H), 4.97 (s, 2H), 4.18-4.16 (m, 4H), 2.53 (s,3H), 2.32 (s, 3H) 424 (M⁺ − 44), 175 (base) Example 7-9  Example 3-2

(DMSO-d₆) δ: 10.15 (br s, 1H), 7.67-7.64 (m, 2H), 7.45 (d, J = 8.1 Hz,1H), 7.33-7.24 (m, 4H), 5.29 (s, 2H), 4.12 (t, J = 6.9 Hz, 2H),2.98-2.94 (m, 2H), 2.68- 2.60 (m, 2H), 2.52 (m, 3H), 2.32 (s, 3H) 418(M⁺) 374, 171 (base) Example 7-12 Example 3-2

(DMSO-d₆) δ: 10.16 (br s, 1H), 7.64 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.39-7.34 (m, 2H), 7.29-7.24 (m, 2H), 5.29 (s,2H), 4.13- 4.10 (m, 2H), 2.98-2.4 (m, 2H), 2.90 (q, J = 7.3 Hz, 2H),2.68-2.60 (m, 2H), 2.31 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H) 388 (M⁺ − 44)159 (base)

TABLE 44 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-8  Example 3-2

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.17 (dd, J = 1.9, 8.1 Hz, 1H), 7.64 (s,1H), 7.46 (d, J = 8.1 Hz, 1H), 7.41- 7.37 (m, 1H), 7.26 (d, J = 8.5 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m, 1H), 5.28 (s, 2H),4.14-4.10 (m, 2H), 3.98 (s, 3H), 2.98- 2.95 (m, 2H), 2.68-2.60 (m, 2H),2.31 (s, 3H) 390 (M⁺ −    44), 159 (base) Example 7-13 Example 3-2

(DMSO-d₆) δ: 10.01 (br s, 1H), 8.18 (dd, J = 6.9, 8.9 Hz, 1H), 7.64 (s,1H), 7.45 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 7.13 (dd, J =2.7, 11.2 Hz, 1H), 6.90 (dt, J = 2.7, 8.5 Hz, 1H), 5.28 (s, 2H), 4.12(t, J = 6.9 Hz, 2H), 4.00 (s, 3H), 2.98- 2.95 (m, 2H), 2.66-2.62 (m,2H), 2.30 (s, 3H) 408 (M⁺ −    44), 159 (base) — Example 3-2

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H),7.45 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 8.1 Hz,1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.12 (t, J = 6.9 Hz,2H), 4.02 (s, 3H), 2.98-2.95 (m, 2H), 2.66-2.62 (m, 2H), 2.31 (s, 3H)424 (M⁺ −    44), 159 (base) Example 7-14 Example 3-2

(DMSO-d₆) δ: 9.94 (br s, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.87(d, J = 8.1 Hz, 1H), 5.27 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 3.96 (s,3H), 2.96 (t, J = 7.3 Hz, 2H), 2.68-2.60 (m, 2H), 2.35 (s, 3H), 2.28 (s,3H) 448 (M⁺),  404, 159 (base)

TABLE 45 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-15 Example 3-2

(DMSO-d₆) δ: 9.87 (br s, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.63 (s, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.26 (d, J = 2.3 Hz,1H), 6.65 (dd, J = 2.3, 8.9 Hz, 1H), 5.27 (s, 2H), 4.11 (t, J = 6.9 Hz,2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.98-2.94 (m, 2H), 2.67-2.60 (m, 2H),2.26 (s, 2H)  276,  188, 159 (base) Example 7-6  Example 3-2

(DMSO-d₆) δ: 10.17 (br s, 1H), 7.71-7.68 (m, 1H), 7.64 (s, 1H), 7.45(dd, J = 3.1, 8.1 Hz, 1H), 7.26-7.17 (m, 2H), 7.12 (dt, J = 2.7, 8.5 Hz,1H), 5.29 (s, 2H), 4.13-4.10 (m, 2H), 2.98-2.94 (m, 2H), 2.68- 2.60 (m,2H), 2.52 (s, 3H), 2.31 (s, 3H) 436 (M⁺),  392, 171 (base) Example 7-7 Example 3-2

(DMSO-d₆) δ: 10.23 (br s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H),7.47- 7.44 (m, 1H), 7.35 (dd, J = 2.3, 8.5 Hz, 1H), 7.25 (dd, J = 2.3,8.5 Hz, 1H), 5.29 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 2.96 (t, J = 7.3Hz, 2H), 2.68-2.60 (m, 2H), 2.53 (s, 3H), 2.32 (s, 3H) 452 (M⁺),  408,159 (base) Example 7-16 Example 3-2

(DMSO-d₆) δ: 10.11 (br s, 1H), 7.64 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 4.11 (t, J = 6.9 Hz, 2H), 2.96 (t, J= 7.3 Hz, 2H), 2.64 (t, J = 6.9 Hz, 2H), 2.50 (s, 3H), 2.31 (s, 6H) 388(M⁺ −    44), 159 (base)

TABLE 46 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-12 —

(DMSO-d₆) δ: 10.15 (brs, 1H), 7.61 (s, 1H), 7.53 (d, J = 7.3 Hz, 1H),7.47 (d, J = 8.5 Hz, 1H), 7.39-7.34 (m, 2H), 7.30-7.26 (m, 2H), 5.29 (s,2H), 4.12-4.09 (m, 2H), 2.97 (t, J = 6.2 Hz, 2H), 2.90 (q, J = 7.3 Hz,2H), 2.31 (s, 3H), 2.07-2.04 (m, 2H), 1.95-1.91 (m, 2H), 1.13 (t, J =7.3 Hz, 3H) 446 (M⁺), 402, 202 (base) Example 7-8  —

(DMSO-d₆) δ: 10.01 (brs, 1H), 8.17 (dd, J = 1.9, 8.1 Hz, 1H), 7.62 (s,1H), 7.47 (d, J = 8.5 Hz, 1H), 7.41-7.37 (m, 1H), 7.29 (d, J = 7.7 Hz,1H), 7.20 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m, 1H), 5.29 (s, 2H),4.11-4.08 (m, 2H), 4.03 (s, 3H), 2.98-2.95 (m, 2H), 2.31 (s, 3H),2.06-2.02 (m, 2H), 1.97-1.92 (m, 2H) 448 (M⁺), 404, 185 (base) Example7-13 —

(DMSO-d₆) δ: 10.02 (brs, 1H), 8.18 (dd, J = 6.9, 8.9 Hz, 1H), 7.61 (s,1H), 7.47 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.29 (s, 2H), 4.10(t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 2.98-2.95 (m, 2H), 2.30 (s, 3H),2.07-2.02 (m, 2H), 1.96-1.90 (m, 2H) 422 (M⁺ − 44), 173 (base) Example7-14 —

(DMSO-d₆) δ: 9.93 (brs, 1H), 8.04 (d, J = 7.7 Hz, 1H), 7.61 (s, 1H),7.47 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.87(dd, J = 0.8, 8.1 Hz, 1H), 5.28 (s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.96(s, 3H), 2.96 (t, J = 6.2 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 2.08-2.02(m, 2H), 1.97-1.91 (m, 2H) 462 (M⁺), 418, 173 (base)

TABLE 47 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-16 —

(DMSO-d₆) δ: 10.10 (brs, 1H), 7.61 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.46 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.14 (s, 1H), 7.10(d, J = 8.5 Hz, 1H), 5.29 (s, 2H), 4.10 (t, J = 5.8 Hz, 2H), 2.96 (t, J= 6.1 Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 2.10-1.99 (m,2H), 1.97-1.92 (m, 2H) 446 (M⁺), 402, 244 (base) Example 7-6  —

(DMSO-d₆) δ: 10.18 (brs, 1H), 7.69 (dd, J = 6.2, 8.9 Hz, 1H), 7.61 (s,1H), 7.46 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 7.7 Hz, 1H), 7.21 (dd, J =2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H), 5.29 (s, 2H),4.11-4.08 (m, 2H), 2.98-2.95 (m, 2H), 2.52 (s, 3H), 2.31 (s, 3H),2.08-2.02 (m, 2H), 1.96-1.90 (m, 2H) 406 (M⁺ − 44), 173 (base) Example7-7  —

(DMSO-d₆) δ: 10.23 (brs, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H),7.46 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 2.3,8.5 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 5.30 (s, 2H), 4.11-4.08 (m, 2H),3.00-2.95 (m, 2H), 2.53 (s, 3H), 2.32 (s, 3H), 2.08-2.02 (m, 2H),1.96-1.91 (m, 2H) 422 (M⁺ − 44), 185 (base) Example 7-13 Example 3-4

(DMSO-d₆) δ: 10.01 (brs, 1H), 8.18 (dd, J = 6.9, 8.9 Hz, 1H), 7.61 (s,1H), 7.53 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.13 (dd, J =2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.28 (s, 2H),4.69-4.65 (m, 1H), 4.00 (s, 3H), 3.02-2.97 (m, 1H), 2.93-2.89 (m, 1H),2.30 (s, 3H), 2.15-2.11 (m, 1H), 2.04-2.01 (m, 1H), 1.91-1.89 (m, 2H),1.43 (d, J = 6.2 Hz, 3H) 436 (M⁺ − 44), 264 (base)

TABLE 48 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/z —Example 3-4

(DMSO-d₆) δ: 10.08 (brs, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.53 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.26 (d, J = 8.5 Hz,1H), 7.12 (dd, J = 2.3, 8.5 Hz, 1H), 5.28 (s, 2H), 4.68-4.65 (m, 1H),4.02 (s, 3H), 3.02-2.97 (m, 1H), 2.93-2.89 (m, 1H), 2.31 (s, 3H),2.15-2.11 (m, 1H), 2.04-2.02 (m, 1H), 1.91-1.89 (m, 2H), 1.43 (d, J =6.6 Hz, 3H) 280, 216 (base) Example 7-16 Example 3-4

(DMSO-d₆) δ: 10.10 (brs, 1H), 7.61 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H),7.53 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 4.69-4.65 (m, 1H), 3.03-2.97 (m, 1H),2.93-2.85 (m, 1H), 2.50 (s, 3H), 2.31 (s, 6H), 2.18-2.10 (m, 1H),2.06-1.98 (m, 1H), 1.91-1.89 (m, 2H), 1.43 (d, J = 6.6 Hz, 3H) 416 (M⁺ −44), 244 (base) Example 7-7  Example 3-4

(DMSO-d₆) δ: 10.23 (brs, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.53 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 2.3,8.5 Hz, 1H), 7.26 (d, J = 7.3 Hz, 1H), 5.29 (s, 2H), 4.69-4.65 (m, 1H),3.01-2.96 (m, 1H), 2.93-2.85 (m, 1H), 2.53 (s, 3H), 2.32 (s, 3H),2.18-2.10 (m, 1H), 2.06-1.98 (m, 1H), 1.91-1.89 (m, 2H), 1.43 (d, J =6.6 Hz, 3H) 264 (base), 216 — Example 3-5

(DMSO-d₆) δ: 10.08 (brs, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H),7.47 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 8.5 Hz,1H), 7.11 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.29-4.23 (m, 1H),4.01 (s, 3H), 3.99-3.93 (m, 1H), 3.10-3.04 (m, 1H), 2.59-2.56 (m, 1H),2.31 (s, 3H), 2.15-2.10 (m, 2H), 1.79-1.69 (m, 1H), 1.12 (d, J = 6.6 Hz,3H) 496 (M⁺), 452, 199 (base)

TABLE 49 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-14 Example 3-5

(DMSO-d₆) δ: 9.93 (brs, 1H), 8.04 (d, J = 8.1 Hz, 1H), 7.61 (s, 1H),7.47 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.02 (s, 1H), 6.87(d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 4.28-4.24 (m, 1H), 4.00-3.95 (m, 1H),3.96 (s, 3H), 3.10-3.04 (m, 1H), 2.70-2.56 (m, 1H), 2.35 (s, 3H), 2.28(s, 3H), 2.15-2.05 (m, 2H), 1.77-1.72 (m, 1H), 1.12 (d, J = 6.6 Hz, 3H)476 (M⁺), 432, 216 (base) Example 7-16 Example 3-5

(DMSO-d₆) δ: 10.10 (brs, 1H), 7.61 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.46 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 4.29-4.23 (m, 1H), 4.00-3.93 (m, 1H),3.10-3.04 (m, 1H), 2.70-2.55 (m, 1H), 2.35 (s, 3H), 2.49 (s, 3H), 2.31(s, 3H), 2.30 (s, 3H), 2.20-2.10 (m, 2H), 1.79-1.69 (m, 1H), 1.12 (d, J= 6.6 Hz, 3H) 416 (M⁺ − 44), 244 (base) — Example 3-3

(DMSO-d₆) δ: 10.07 (brs, 1H), 8.16 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.53 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 9.2 Hz,1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.28 (s, 2H), 4.27-4.24 (m, 2H),4.01 (s, 3H), 3.04-3.02 (m, 2H), 2.31 (s, 3H), 1.88-1.85 (m, 2H),1.75-1.71 (m, 2H), 1.70-1.65 (m, 2H) 496 (M⁺), 452, 280, 216 (base)Example 7-16 Example 3-3

(DMSO-d₆) δ: 10.09 (brs, 1H), 7.60 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H),7.52 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 8.1 Hz, 1H), 5.28 (s, 2H), 4.26-4.24 (m, 2H), 3.04-3.02 (m, 2H),2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.91-1.85 (m, 2H), 1.75-1.71(m, 2H), 1.70-1.66 (m, 2H) 416 (M⁺ − 44), 244 (base)

TABLE 50 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-12 Example 4-1

(DMSO-d₆) δ: 10.17 (brs, 1H), 8.08 (s, 1H), 7.85 (s, 1H), 7.67 (d, J =8.9 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H),7.42-7.38 (m, 2H), 7.30-7.26 (m, 1H), 5.31 (s, 2H), 4.06 (s, 3H), 2.90(q, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.13 (t, J = 7.3 Hz, 3H) 406 (M⁺),362, 145 (base) Example 7-8  Example 4-1

(DMSO-d₆) δ: 10.02 (brs, 1H), 8.18 (dd, J = 1.9, 8.1 Hz, 1H), 8.08 (s,1H), 7.85 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H),7.41-7.37 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.06 (dt, J = 1.2, 8.1 Hz,1H), 5.30 (s, 2H), 4.06 (s, 3H), 3.98 (s, 3H), 2.31 (s, 3H) 408 (M⁺),364, 145 (base) Example 7-13 Example 4-1

(DMSO-d₆) δ: 10.04 (brs, 1H), 8.18 (dd, J = 6.9, 8.9 Hz, 1H), 8.08 (d, J= 0.8 Hz, 1H), 7.84 (s, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.9Hz, 1H), 7.13 (dd, J = 2.7, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz,1H), 5.30 (s, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 2.30 (s, 3H) 426 (M⁺),382, 145 (base) — Example 4-1

(DMSO-d₆) δ: 10.10 (brs, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H),7.85 (s, 1H), 7.68 (d, J = 8.9 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.30(d, J = 1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.30 (s, 2H), 4.06(s, 3H), 4.02 (s, 3H), 2.31 (s, 3H) 442 (M⁺), 398, 145 (base)

TABLE 51 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-14 Example 4-1

(DMSO-d₆) δ: 9.96 (brs, 1H), 8.07 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 8.1Hz, 1H), 7.84 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.5 Hz,1H), 7.02 (s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.29 (s, 2H), 4.06 (s, 3H),3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H) 422 (M⁺), 378, 145 (base)Example 7-16 Example 4-1

(DMSO-d₆) δ: 10.12 (brs, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.67 (d, J =8.5 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.48 (d, J = 8.1 Hz, 1H),7.37-7.32 (m, 1H), 7.14 (s, 1H), 5.30 (s, 2H), 4.06 (s, 3H), 2.50 (s,3H), 2.31 (s, 6H) 406 (M⁺), 362, 145 (base) Example 7-5  Example 4-1

(DMSO-d₆) δ: 10.34 (brs, 1H), 8.19-8.15 (m, 1H), 8.08 (s, 1H), 7.85 (s,1H), 7.61 (dd, J = 2.7, 8.9 Hz, 1H), 7.49 (dd, J = 1.2, 8.5 Hz, 1H),7.35 (ddd, J = 2.7, 8.1, 8.9 Hz, 1H), 5.32 (s, 2H), 4.06 (s, 3H), 2.34(s, 3H) 386 (M⁺ − 44), 145 (base) Example 7-19 Example 4-1

(DMSO-d₆) δ: 9.79 (brs, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.52-7.44 (m,1H), 7.36-7.34 (m, 1H), 5.25 (s, 2H), 4.05 (s, 3H), 2.45-2.38 (m, 1H),2.17 (s, 3H), 1.87-1.84 (m, 1H), 1.77-1.68 (m, 4H), 1.59-1.57 (m, 1H),1.48-1.39 (m, 1H), 1.38-1.26 (m, 1H), 1.14-1.03 (m, 1H), 0.74 (d, J =6.2 Hz, 3H) 398 (M⁺), 354, 145 (base) Example 7-12 Example 4-3

(DMSO-d₆) δ: 10.17 (brs, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.70 (d, J =8.9 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H),7.37-7.34 (m, 2H), 7.30-7.26 (m, 1H), 5.30 (s, 2H), 4.45 (q, J = 7.3 Hz,2H), 2.90 (q, J = 7.3 Hz, 2H), 2.31 (s, 3H), 1.39 (t, J = 7.3 Hz, 3H),1.12 (t, J = 7.3 Hz, 3H) 420 (M⁺), 376, 159 (base)

TABLE 52 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-8  Example 4-3

(DMSO-d₆) δ: 10.01 (brs, 1H), 8.17 (dd, J = 1.9, 8.1 Hz, 1H), 8.09 (s,1H), 7.85 (s, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H),7.41-7.37 (m, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08-7.04 (m, 1H), 5.30 (s,2H), 4.45 (q, J = 7.3 Hz, 2H), 3.98 (s, 3H), 2.31 (s, 3H), 1.40 (t, J =7.3 Hz, 3H) 422 (M⁺), 378, 159 (base) Example 7-13 Example 4-3

(DMSO-d₆) δ: 10.01 (brs, 1H), 8.18 (dd, J = 7.3, 8.9 Hz, 1H), 8.09 (s,1H), 7.84 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H),7.13 (dd, J = 2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.3, 8.5 Hz, 1H), 5.29(s, 2H), 4.45 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 2.30 (s, 3H), 1.39 (t,J = 7.3 Hz, 3H) 440 (M⁺), 396, 159 (base) — Example 4-3

(DMSO-d₆) δ: 10.10 (brs, 1H), 8.16 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H),7.84 (s, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.30(d, J = 1.9 Hz, 1H), 7.12 (dd, J = 2.3 Hz, 8.5 Hz, 1H), 5.30 (s, 2H),4.45 (q, J = 7.3 Hz, 2H), 4.01 (s, 3H), 2.31 (s, 3H), 1.39 (t, J = 7.3Hz, 3H) 456 (M⁺), 412, 159 (base) Example 7-14 Example 4-3

(DMSO-d₆) δ: 9.95 (brs, 1H), 8.09 (s, 1H), 8.04 (d, J = 8.1 Hz, 1H),7.84 (s, 1H), 7.71 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.02(s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 4.46 (q, J = 7.3 Hz,2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 1.39 (t, J = 7.3 Hz, 3H)436 (M⁺), 396, 159 (base) Example 7-15 Example 4-3

(DMSO-d₆): 9.88 (brs, 1H), 8.09 (s, 1H), 8.07 (s, 1H), 7.84 (s, 1H),7.70 (d, J = 8.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 2.3 Hz,1H), 6.66 (dd, J = 2.3, 8.5 Hz, 1H), 5.28 (s, 2H), 4.45 (q, J = 7.3 Hz,2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H), 1.39 (t, J = 7.3 Hz, 3H)452 (M⁺), 408, 159 (base)

TABLE 53 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-16 Example 4-3

(DMSO-d₆) δ: 10.12 (brs, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.70 (d, J =8.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.14(s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.30 (s, 2H), 4.45 (q, J = 7.3 Hz,2H), 4.06 (s, 3H), 2.50 (s, 3H), 2.31 (s, 3H), 2.30 (s, 3H), 1.39 (t, J= 7.3 Hz, 3H) 420 (M⁺), 376, 159 (base) Example 7-6  Example 4-3

(DMSO-d₆) δ: 10.19 (brs, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.70 (d, J =8.5 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.51-7.45 (m, 1H), 7.21 (dd, J =2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H), 5.30 (s, 2H), 4.45(q, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.31 (s, 3H), 1.39 (t, J = 7.3 Hz,3H) 424 (M⁺), 380, 159 (base) Example 7-7  Example 4-3

(DMSO-d₆) δ: 10.24 (brs, 1H), 8.09 (s, 1H), 7.71 (s, 1H), 7.69 (s, 1H),7.71 (d, J = 8.9 Hz, 1H), 7.51-7.44 (m, 2H), 7.36-7.32 (m, 1H), 5.31 (s,2H), 4.45 (q, J = 7.3 Hz, 2H), 2.51 (s, 3H), 2.32 (s, 3H), 1.39 (t, J =7.3 Hz, 3H) 440 (M⁺), 396, 159 (base) Example 7-12 Example 4-2

(DMSO-d₆) δ: 10.18 (brs, 1H), 8.37 (s, 1H), 7.78 (s, 1H), 7.62 (d, J =8.9 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40-7.34 (m, 2H), 7.30-7.26 (m,2H), 5.25 (s, 2H), 4.17 (s, 3H), 2.91 (q, J = 7.3 Hz, 2H), 2.32 (s, 3H),1.13 (t, J = 7.3 Hz, 3H) 406 (M⁺), 362, 145 (base) Example 7-13 Example4-2

(DMSO-d₆) δ: 10.04 (brs, 1H), 8.37 (s, 1H), 8.18 (dd, J = 7.3, 8.9 Hz,1H), 7.77 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H),7.13 (dd, J = 2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.7, 8.5 Hz, 1H), 5.24(s, 2H), 4.17 (s, 3H), 4.00 (s, 3H), 2.30 (s, 3H) 426 (M⁺), 382, 145(base)

TABLE 54 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/z —Example 4-2

(DMSO-d₆) δ: 10.11 (brs, 1H), 8.37 (s, 1H), 8.17 (d, J = 8.9 Hz, 1H),7.78 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.34-7.28 (m, 2H), 7.12 (dd, J =1.9, 8.5 Hz, 1H), 5.25 (s, 2H), 4.17 (s, 3H), 4.02 (s, 3H), 2.31 (s, 3H)442 (M⁺), 398, 145 (base) Example 7-14 Example 4-2

(DMSO-d₆) δ: 9.96 (brs, 1H), 8.37 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H),7.77 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.02(s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.23 (s, 2H), 4.17 (s, 3H), 3.96 (s,3H), 2.35 (s, 3H), 2.29 (s, 3H) 422 (M⁺), 378, 145 (base) Example 7-15Example 4-2

(DMSO-d₆) δ: 9.89 (brs, 1H), 8.36 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H),7.77 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 6.73(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.9 Hz, 1H), 5.23 (s, 2H), 4.17(s, 3H), 3.97 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H) 438 (M⁺), 394, 145(base) Example 7-16 Example 4-2

(DMSO-d₆) δ: 10.13 (brs, 1H), 8.37 (s, 1H), 7.77 (s, 1H), 7.62 (d, J =8.9 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),7.14 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.24 (s, 2H), 4.17 (s, 3H), 2.50(s, 3H), 2.31 (s, 6H) 406 (M⁺), 362, 145 (base) Example 7-5  Example 4-2

(DMSO-d₆) δ: 10.34 (brs, 1H), 8.37 (s, 1H), 8.17 (dd, J = 6.2, 8.9 Hz,1H), 7.78 (s, 1H), 7.63-7.59 (m, 1H), 7.35 (dt, J = 2.7, 8.9 Hz, 1H),7.30 (d, J = 8.9 Hz, 1H), 5.24 (s, 2H), 4.17 (s, 3H), 2.34 (s, 3H) 386(M⁺ − 44), 145 (base)

TABLE 55 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-6  Example 4-2

(DMSO-d₆) δ: 10.20 (brs, 1H), 8.36 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J =6.3, 8.7 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.29 (d, J = 9.2 Hz, 1H),7.21 (dd, J = 2.4, 10.1 Hz, 1H), 7.12 (dt, J = 2.9, 8.7 Hz, 1H), 5.25(s, 2H), 4.17 (s, 3H), 2.52 (s, 3H), 2.32 (s, 3H) 410 (M⁺), 366, 145(base) Example 7-7  Example 4-2

(DMSO-d₆) δ: 10.25 (brs, 1H), 8.37 (s, 1H), 7.78 (s, 1H), 7.70 (d, J =8.2 Hz, 1H), 7.63 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.35(dd, J = 2.4, 8.7 Hz, 1H), 7.30 (dd, J = 2.0, 8.7 Hz, 1H), 5.25 (s, 2H),4.17 (s, 3H), 2.53 (s, 3H), 2.32 (s, 3H) 426 (M⁺), 382, 145 (base)Example 7-12 Example 4-4

(DMSO-d₆) δ: 10.17 (brs, 1H), 8.41 (s, 1H), 7.78 (s, 1H), 7.63 (d, J =8.9 Hz, 1H), 7.53 (d, J = 7.3 Hz, 1H), 7.40-7.34 (m, 2H), 7.30-7.26 (m,2H), 5.25 (s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 2.91 (q, J = 7.3 Hz, 2H),2.32 (s, 3H), 1.51 (t, J = 7.3 Hz, 3H), 1.13 (t, J = 7.3 Hz, 3H) 420(M⁺), 376, 159 (base) Example 7-8  Example 4-4

(DMSO-d₆) δ: 10.03 (brs, 1H), 8.41 (s, 1H), 8.18 (dd, J = 1.9, 8.1 Hz,1H), 7.78 (s, 1H), 7.64 (d, J = 8.9 Hz, 1H), 7.41-7.37 (m, 1H),7.31-7.29 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m, 1H), 5.25 (s,2H), 4.46 (q, J = 7.3 Hz, 2H), 3.98 (s, 3H), 2.31 (s, 3H), 1.51 (t, J =7.3 Hz, 3H) 422 (M⁺), 378, 159 (base) Example 7-13 Example 4-4

(DMSO-d₆) δ: 10.03 (brs, 1H), 8.41 (s, 1H), 8.18 (dd, J = 6.9, 8.9 Hz,1H), 7.77 (s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.30 (dd, J = 1.5, 8.9 Hz,1H), 7.13 (dd, J = 2.3, 11.2 Hz, 1H), 6.90 (dt, J = 2.7, 8.5 Hz, 1H),5.24 (s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 2.30 (s, 3H), 1.51(t, J = 7.3 Hz, 3H) 440 (M⁺), 396, 159 (base)

TABLE 56 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/z —Example 4-4

(DMSO-d₆) δ: 10.10 (brs, 1H), 8.41 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H),7.78 (s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.30-7.28 (m, 2H), 7.12 (dd, J =2.3, 8.5 Hz, 1H), 5.25 (s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 4.02 (s, 3H),2.31 (s, 3H), 1.51 (t, J = 7.3 Hz, 3H) 456 (M⁺), 412, 159 (base) Example7-14 Example 4-4

(DMSO-d₆) δ: 9.96 (brs, 1H), 8.41 (s, 1H), 8.05 (d, J = 8.1 Hz, 1H),7.77 (s, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.30 (dd, J = 1.2, 8.9 Hz, 1H),7.02 (s, 1H), 6.87 (d, J = 7.3 Hz, 1H), 5.24 (s, 2H), 4.46 (q, J = 7.3Hz, 2H), 3.96 (s, 3H), 2.35 (s, 3H), 2.29 (s, 3H), 1.51 (t, J = 7.3 Hz,3H) 436 (M⁺), 392, 159 (base) Example 7-15 Example 4-4

(DMSO-d₆) δ: 9.89 (brs, 1H), 8.41 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H),7.77 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 6.73(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.9 Hz, 1H), 5.23 (s, 2H), 4.46(q, J = 7.3 Hz, 2H), 3.97 (s, 3H), 3.83 (s, 3H), 2.27 (s, 3H), 1.51 (t,J = 7.3 Hz, 3H) 452 (M⁺), 408, 159 (base) Example 7-16 Example 4-4

(DMSO-d₆) δ: 10.12 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.63 (d, J =8.9 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),7.14 (s, 1H), 7.10 (d, J = 8.9 Hz, 1H), 5.24 (s, 2H), 4.46 (q, J = 7.3Hz, 2H), 2.50 (s, 3H), 2.31 (s, 6H), 1.51 (t, J = 7.3 Hz, 3H) 420 (M⁺),376, 159 (base) Example 7-6  Example 4-4

(DMSO-d₆) δ: 10.20 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J =6.2, 8.5 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 0.8, 8.9 Hz,1H), 7.21 (dd, J = 2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.5 Hz, 1H),5.25 (s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H), 1.51(t, J = 7.3 Hz, 3H) 424 (M⁺), 380, 159 (base)

TABLE 57 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-7  Example 4-4

(DMSO-d₆) δ: 10.25 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.70 (d, J =8.5 Hz, 1H), 7.63 (d, J = 8.9 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.35(dd, J = 1.9, 8.9 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.25 (s, 2H), 4.46(q, J = 7.3 Hz, 2H), 2.52 (s, 3H), 2.32 (s, 3H), 1.51 (t, J = 7.3 Hz,3H) 396 (M⁺ − 44), 159 (base) Example 7-28 Example 5-1

(DMSO-d₆) δ: 10.11 (brs, 1H), 8.19 (d, J = 8.5 Hz, 1H), 8.13 (s, 1H),7.94 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.30 (d, J = 1.9 Hz,1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.37 (s, 2H), 4.75 (q, J = 7.3 Hz,2H), 4.01 (s, 3H), 2.75-2.70 (m, 2H), 1.52 (t, J = 7.3 Hz, 3H), 1.81 (t,J = 7.3 Hz, 3H) 471 (M⁺), 427, 104 (base) Example 7-27 Example 1-1

(DMSO-d₆) δ: 9.98 (brs, 1H), 8.21 (s, 1H), 8.19 (d, J = 1.9 Hz, 1H),7.75 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 1.9, 7.3 Hz, 1H),7.36 (dd, J = 1.5, 8.1 Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.09-7.04 (m,1H), 5.31 (s, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 2.68 (q, J = 7.3 Hz, 2H),1.18 (t, J = 7.3 Hz, 3H) 422 (M⁺), 378, 260, 145 (base) Example 7-27Example 1-2

(DMSO-d₆) δ: 9.97 (brs, 1H), 8.28 (d, J = 2.7 Hz, 1H), 8.19 (dd, J =1.9, 8.1 Hz, 1H), 7.75 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.41-7.34 (m,2H), 7.20 (d, J = 8.5 Hz, 1H), 7.08-7.04 (m, 1H), 5.30 (s, 2H), 4.29 (q,J = 7.3 Hz, 2H), 3.98 (s, 3H), 2.75-2.65 (m, 2H), 1.42 (t, J = 7.3 Hz,3H), 1.18 (t, J = 7.3 Hz, 3H) 436 (M⁺), 392, 260 (base) Example 7-30Example 1-1

(DMSO-d₆) δ: 10.15 (brs, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.69 (dd, J =6.2, 8.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H),7.21 (dd, J = 2.7, 10.0 Hz, 1H), 7.12 (dt, J = 2.7, 8.9 Hz, 1H), 5.31(s, 2H), 3.85 (s, 3H), 2.69 (q, J = 7.3 Hz, 2H), 2.53 (s, 3H), 1.18 (t,J = 7.3 Hz, 3H) 424 (M⁺), 380, 145 (base)

TABLE 58 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-28 Example 1-2

(DMSO-d₆) δ: 10.06 (brs, 1H), 8.27 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.30(d, J = 2.3 Hz, 1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.30 (s, 2H), 4.29(q, J = 7.3 Hz, 2H), 4.01 (s, 3H), 2.72-2.66 (m, 2H), 1.42 (t, J = 7.3Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H) 470 (M⁺), 426, 294 (base) Example 7-31Example 1-2

(DMSO-d₆) δ: 9.90 (brs, 1H), 8.27 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H),7.74 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.02(s, 1H), 6.88 (d, J = 7.7 Hz, 1H), 5.29 (s, 2H), 4.29 (q, J = 7.3 Hz,2H), 3.96 (s, 3H), 2.69-2.64 (m, 2H), 2.36 (s, 3H), 1.42 (t, J = 7.3 Hz,3H), 1.17 (t, J = 7.3 Hz, 3H) 450 (M⁺), 406, 147 (base) Example 7-29Example 1-2

(DMSO-d₆) δ: 10.07 (brs, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 7.14(s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H), 4.29 (q, J = 7.3 Hz,2H), 2.67 (q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.41 (t, J =7.3 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H) 434 (M⁺), 258 (base) Example 7-30Example 1-2

(DMSO-d₆) δ: 10.15 (brs, 1H), 8.27 (s, 1H), 7.74 (s, 1H), 7.69 (dd, J =5.8, 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.5 Hz, 1H),7.21 (dd, J = 2.7, 10.0 Hz, 1H), 7.13 (dt, J = 2.7, 8.5 Hz, 1H), 5.31(s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 2.75-2.65 (m, 2H), 2.53 (s, 3H), 1.42(t, J = 7.3 Hz, 3H), 1.18 (t, J = 7.3 Hz, 3H) 438 (M⁺), 394, 159 (base)

TABLE 59 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-27 Example 3-6

(DMSO-d₆) δ: 9.96 (brs, 1H), 8.20 (dd, J = 1.9, 8.1 Hz, 1H), 7.69 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.33 (d, J = 8.1 Hz,1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08-7.04 (m, 1H), 5.30 (s, 2H), 4.96 (s,2H), 4.21-4.17 (m, 4H), 3.98 (s, 3H), 2.68 (q, J = 7.3 Hz, 2H),1.20-1.16 (m, 3H) 464 (M⁺), 420, 187 (base) Example 7-28 Example 3-6

(DMSO-d₆) δ: 10.07 (brs, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz,1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.30 (s, 2H), 4.96 (s, 2H),4.22-7.15 (m, 4H), 4.01 (s, 3H), 2.75-2.65 (m, 2H), 1.17 (t, J = 7.3 Hz,3H) 498 (M⁺), 454, 204 (base) Example 7-28 Example 3-2

(DMSO-d₆) δ: 10.06 (brs, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.64 (s, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 8.5 Hz,1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.28 (s, 2H), 4.12 (t, J = 6.9 Hz,2H), 4.02 (s, 3H), 2.98-2.94 (m, 2H), 2.72-2.60 (m, 4H), 1.71 (t, J =7.3 Hz, 3H) 482 (M⁺), 436, 159 (base) Example 7-31 Example 3-2

(DMSO-d₆) δ: 9.90 (brs, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.63 (s, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 6.88(d, J = 8.1 Hz, 1H), 5.27 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 3.96 (s,3H), 2.96 (t, J = 7.3 Hz, 2H), 2.68-2.60 (m, 4H), 2.35 (s, 3H),1.20-1.15 (m, 6H) 462 (M⁺), 418, 171 (base)

TABLE 60 Carboxylic Hydroxy acid compound Example ¹H-NMR Mass, m/zExample 7-28 —

(DMSO-d₆) δ: 10.05 (brs, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.61 (s, 1H),7.47 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 7.7 Hz,1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.10 (t, J = 6.2 Hz,2H), 4.01 (s, 3H), 2.98-2.95 (m, 2H), 2.69 (q, J = 7.3 Hz, 2H),2.08-2.02 (m, 2H), 1.97-1.91 (m, 2H), 1.17 (t, J = 7.3 Hz, 3H) 496 (M⁺),452, 202 (base) Example 7-28 Example 4-3

(DMSO-d₆) δ: 10.06 (brs, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H),7.84 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.30(d, J = 2.3 Hz, 1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.29 (s, 2H), 4.45(q, J = 7.3 Hz, 2H), 4.01 (s, 3H), 2.75-2.65 (m, 2H), 1.39 (t, J = 7.3Hz, 3H), 1.17 (t, J = 7.3 Hz, 3H) 470 (M⁺), 426, 159 (base) Example 7-31Example 4-3

(DMSO-d₆) δ: 9.91 (brs, 1H), 8.09 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H),7.84 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.02(s, 1H), 6.88 (d, J = 8.5 Hz, 1H), 5.28 (s, 2H), 4.45 (q, J = 7.3 Hz,2H), 3.96 (s, 3H), 2.75-2.65 (m, 2H), 2.36 (s, 3H), 1.39 (t, J = 7.3 Hz,3H), 1.17 (t, J = 7.3 Hz, 3H) 450 (M⁺), 406, 159 (base) Example 7-29Example 4-3

(DMSO-d₆) δ: 10.08 (brs, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.70 (d, J =8.9 Hz, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.14(s, 1H), 7.10 (d, J = 8.1 Hz, 1H), 5.29 (s, 2H), 4.45 (q, J = 7.3 Hz,2H), 2.67 (q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.39 (t, J =7.3 Hz, 3H), 1.71 (t, J = 7.3 Hz, 3H) 434 (M⁺), 390, 159 (base)

TABLE 61 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-176 Example 7-28 Example 4-4

(DMSO-d6) δ :10.07 (brs, 1H), 8.41 (s, 1H), 8.19 (d, J = 8.5Hz, 1H),7.77 (s, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.30-7.28 (m, 2H), 7.13 (dd, J =1.9, 8.5Hz, 1H), 5.24 (s, 2H), 4.46 (q, J = 7.3Hz, 2H), 4.01 (s, 3H),2.75-2.65 (m, 2H), 1.51 (t, J = 7.3Hz, 3 H), 1.17 (t, J = 7.3Hz, 3H) 470(M⁺), 426, 159 (base) Example 9-177 Example 7-32 Example 1-2

(DMSO-d₆) δ :10.91 (brs, 1H), 8.27 (s, 1H), 8.17 (d, J = 8.5Hz, 1H),7.74 (s, 1H), 7.64 (d, J = 8.1Hz, 1H), 7.48 (s, 1H), 7.35 (dd, J = 1.5,8.5Hz, 1H), 7.31 (d, J = 1.9Hz, 1H), 7.13 (dd, J = 1.9, 8.5Hz, 1H), 5.32(s, 2H), 4.29 (q, J = 7.3Hz, 2H), 4.03 (s, 3H), 1.41 (t, J = 7.3Hz, 3H)398 (M⁺ − 44), 147 (base) Example 9-178 Example 7-33 Example 1-1

(DMSO-d₆) δ :10.84 (brs, 1H), 8.21 (s, 1H), 8.18 (dd, J = 1.5, 8.1Hz,1H), 7.74 (s, 1H), 7.60 (d, J = 8.5Hz, 1H), 7.47 (s, 1H), 7.41- 7.36 (m,2H), 7.21 (d, J = 8.1Hz, 1H), 7.08-7.04 (m, 1H), 5.32 (s, 2H), 4.00 (s,3H), 3.85 (s, 3H) 394 (M⁺), 350, 133 (base) Example 9-179 Example 7-33Example 4-3

(CDCl₃) δ :8.29 (dd, J = 1.5, 7.7Hz, 1H), 7.98 (s, 1H), 7.77(s, 1 H),7.49 (s, 1H), 7.43 (s, 1H), 7.42 (s, 1H), 7.37-7.32 (m, 1H), 7.07-7.03(m, 1H), 7.00 (d, J = 8.1Hz, 1H), 5.35 (s, 2 H), 4.44 (q, J = 7.3Hz,2H), 4.01 (s, 3H), 1.50 (t, J = 7.3Hz, 3H) 408 (M⁺), 364, 159 (base)

TABLE 62 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-33 Example 4-4

(CDCl₃) δ: 8.29 (dd, J = 1.5, 7.7 Hz, 1H), 7.93 (s, 1H), 7.71 (d, J =9.6 Hz, 1H), 7.70 (s, 1H), 7.49 (s, 1H), 7.37-7.32 (m, 1H), 7.29 (dd, J= 1.5, 8.9 Hz, 1H), 7.07-7.03 (m, 1H), 7.00 (d, J = 8.1 Hz, 1H), 5.30(d, J = 5.0 Hz, 2H), 4.48 (q, J = 7.3 Hz, 2H), 4.01 (s, 3H), 1.63 (t, J= 7.3 Hz, 3H) 364 (M⁺ − 44), 159 (base) Example 7-28 Example 1-1

(DMSO-d₆) δ: 10.06 (brs, 1H), 8.21 (s, 1H), 8.19 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.9 Hz, 1H), 7.30(d, J = 1.9 Hz, 1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H), 4.01(s, 3H), 3.85 (s, 3H), 2.69 (q, J = 7.3 Hz, 2H), 1.17 (t, J = 7.3 Hz,3H) 4.12 (M⁺ − 44), 133 (base) Example 7-29 Example 1-1

(CDCl₃) δ: 7.90 (s, 1H), 7.85 (s, 1H), 7.55 (d, J = 8.1 Hz, 1H), 7.40(brs, 2H), 7.07 (s, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.75 (brs, 1H), 5.36(s, 2H), 3.85 (s, 3H), 2.66 (q, J = 7.3 Hz, 2H), 2.53 (s, 3H), 2.33 (s,3H), 1.28 (t, J = 7.3 Hz, 3H) 4.20 (M⁺), 376, 145 (base) Example 7-34Example 1-1

(DMSO-d₆) δ: 10.07 (brs, 1H), 8.21 (s, 1H), 8.17 (d, J = 8.5 Hz, 1H),7.75 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.30(d, J = 2.3 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.31 (s, 2H), 4.01(s, 3H), 3.85 (s, 3H), 2.66 (t, J = 7.3 Hz, 2H), 1.62 (sextet, J = 7.3Hz, 2H), 0.89 (t, J = 7.3 Hz, 3H) 426 (M⁺ − 44), 133 (base)

TABLE 63 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-35 Example 1-1

(CDCl₃) δ: 7.90 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 7.40(brs, 2H), 7.06 (s, 1H), 7.03 (d, J = 8.1 Hz, 1H), 6.73 (brs, 1H), 5.36(s, 2H), 3.86 (s, 3H), 2.60 (t, J = 7.7 Hz, 2H), 2.52 (s, 3H), 2.33 (s,3H), 1.76-1.71 (m, 2H), 0.95 (t, J = 7.3 Hz 3H) 434 (M⁺), 390, 145(base) Example 7-36 Example 1-1

(CDCl₃) δ: 7.91 (s, 1H), 7.87 (s, 1H), 7.52 (d, J = 7.7 Hz, 1H), 7.41(brs, 2H), 7.05 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.93 (brs, 1H), 5.38(s, 2H), 3.86 (s, 3H), 2.50 (s, 3H), 2.32 (s, 3H), 1.85-1.68 (m, 1H),1.00-0.97 (m, 2H), 0.95-0.91 (m, 2H) 432 (M⁺), 388, 270 (base) Example7-37 Example 1-1

(DMSO-d₆) δ: 10.83 (brs, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.74 (d, J =8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H),7.42-7.39 (m, 1H), 5.37 (s, 2H), 3.85 (s, 3H), 2.53 (s, 3H) 318, 162,145 (base) Example 7-21 Example 1-1

(CDCl₃) δ: 7.89 (s, 1H), 7.84 (s, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.39(brs, 1H), 6.97 (brs, 1H), 6.86 (d, J = 3.5 Hz, 1H), 6.48 (dd, J = 1.5,3.5 Hz, 1H), 5.36 (s, 2H), 3.85 (s, 3H), 2.32 (s, 3H) 368 (M⁺), 145(base)

TABLE 64 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-22 Example 1-1

(CDCl₃) δ: 7.88 (s, 2H), 7.84 (s, 1H), 7.44-7.44 (m, 1H), 7.39 (s, 2H),6.89 (brs, 1H), 6.76 (d, J = 1.2 Hz, 1H), 5.36 (s, 2H), 3.85 (s, 3H),2.31 (s, 3H) 368 (M⁺ − 44), 145 (base) Example 7-21 Example 4-1

(CDCl₃) δ: 7.98 (s, 1H), 7.77 (s, 1H), 7.46-7.36 (m, 3H), 6.86 (d, J =3.5 Hz, 1H), 6.68 (brs, 1H), 6.48 (dd, J = 1.5, 3.5 Hz, 1H), 5.34 (s,2H), 4.08 (s, 3H), 2.31 (s, 3H) 368 (M⁺), 145 (base) Example 7-22Example 4-1

(CDCl₃) δ: 7.98 (s, 1H), 7.90 (dd, J = 0.8, 1.5 Hz, 1H), 7.78 (s, 1H),46-7.40 (m, 3H), 6.76 (d, J = 1.2 Hz, 1H), 6.64 (brs, 1H), 5.33 (s, 2H),4.08 (s, 3H), 2.30 (s, 3H) 368 (M⁺), 324, 145 (base) Example 7-23Example 1-1

(CDCl₃) δ: 7.89 (s, 1H), 7.85 (s, 1H), 7.40-7.38 (m, 3H), 7.32 (dd, J =0.8, 5.4 Hz, 1H), 7.03 (dd, J = 3.9, 5.0 Hz, 1H), 5.36 (s, 2H), 3.85 (s,3H), 2.31 (s, 3H) 340 (M⁺ − 44), 222 (base) Example 7-24 Example 1-1

(DMSO-d₆) δ: 10.37 (brs, 1H), 8.21 (s, 1H), 7.75 (s, 1H), 7.71 (d, J =5.4 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.18(d, J = 5.4 Hz, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 2.30 (s, 3H) 374 (M⁺ −44), 145 (base)

TABLE 65 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-25 Example 1-1

(DMSO-d₆) δ: 10.36 (brs, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.38 (d, J = 3.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.14(d, J = 3.9 Hz, 1H), 5.32 (s, 2H), 3.85 (s, 3H), 2.26 (s, 3H) 374 (M⁺ −44), 145 (base) Example 7-23 Example 4-1

(CDCl₃) δ: 7.98 (s, 1H), 7.77 (s, 1H), 7.46-7.38 (m, 2H), 7.33-7.32 (m,1H), 7.03 (dd, J = 3.9, 5.0 Hz, 1H), 6.74 (brs, 1H), 5.33 (s, 2H), 4.08(s, 3H), 2.30 (s, 3H) 384 (M⁺), 340, 145 (base) Example 7-39 Example 1-1

(DMSO-d₆) δ: 10.21 (brs, 1H), 8.43-8.41 (m, 1H), 8.21 (s, 1H), 7.76 (s,1H), 7.72 (dd, J = 0.8, 7.7 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.38 (d,J = 7.7 Hz, 1H), 7.29 (dd, J = 4.6, 7.7 Hz, 1H), 5.33 (s, 2H), 3.85 (s,3H), 2.69 (s, 3H), 2.34 (s, 3H) 393 (M⁺), 349, 231 (base) Example 7-39Example 1-2

(DMSO-d₆) δ: 10.20 (brs, 1H), 8.42 (dd, J = 1.2, 4.6 Hz, 1H), 8.27 (s,1H), 7.76 (s, 1H), 7.72 (d, J = 6.9 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H),7.37 (d, J = 7.3 Hz, 1H), 7.30 (dd, J = 4.6, 7.7 Hz, 1H), 5.33 (s, 2H),4.29 (q, J = 7.3 Hz, 2H), 2.69 (s, 3H), 2.34 (s, 3H), 1.42 (t, J = 7.3Hz, 3H) 407 (M⁺), 363, 231 (base) Example 7-26 Example 1-1

(DMSO-d₆) δ: 9.80 (brs, 1H), 8.21 (s, 1H), 7.76 (s, 1H), 7.71 (s, 1H),7.58 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), 3.85(s, 3H), 2.49 (s, 3H), 2.16 (s, 3H) 316 (M⁺), 272, 145 (base)

TABLE 66 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 7-26 —

(DMSO-d₆) δ: 9.79 (brs, 1H), 7.59 (s, 1H), 7.47 (d, J = 8.1 Hz, 1H),7.47 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 5.24 (s, 2H), 4.10(t, J = 6.2 Hz, 2H), 2.96 (t, J = 6.2 Hz, 2H), 2.49 (s, 3H), 2.15 (s,3H), 2.08-2.02 (m, 2H), 1.97-1.91 (m, 2H) 312 (M⁺ − 44), 185 (base)Example 7-26 Example 3-6

(DMSO-d₆) δ: 9.80 (brs, 1H), 7.66 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H),7.30 (d, J = 8.1 Hz, 1H), 5.26 (s, 2H), 4.96 (s, 2H), 4.22-4.15 (m, 4H),2.49 (s, 3H), 2.16 (s, 6H) 358 (M⁺), 314, 187 (base) — Example 6-1

(DMSO-d₆) δ: 10.23 (brs, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H),8.00 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 1.9 Hz,1H), 7.12 (dd, J = 2.3, 8.5 Hz, 1H), 5.43 (s, 2H), 4.01 (s, 3H), 2.69(s, 6H), 2.34 (s, 3H) 468 (M⁺), 171 (base) Example 7-16 Example 6-1

(DMSO-d₆) δ: 10.25 (brs, 1H), 8.03 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H),7.77 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.10(d, J = 8.5 Hz, 1H), 5.43 (s, 2H), 2.69 (s, 6H), 2.50 (s, 3H), 2.33 (s,3H), 2.31 (s, 3H) 432 (M⁺), 171 (base) Example 8-4 4-Methoxy benzylalcohol

(DMSO-d₆) δ: 9.72 (brs, 1H), 7.52-7.48 (m, 1H), 7.38 (d, J = 8.5 Hz,2H), 7.25-7.18 (m, 3H), 6.96 (d, J = 8.5 Hz, 2H), 6.37 (s, 1H), 5.11 (s,2H), 3.77 (s, 3H), 3.70 (s, 3H), 2.43 (s, 3H) 351 (M⁺), 307, 121 (base)

TABLE 67 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-33 4-Methoxy benzyl alcohol

(DMSO-d₆) δ: 9.64 (brs, 1H), 7.82 (dd, J = 7.3, 8.9 Hz, 1H), 7.37 (d, J= 8.5 Hz, 2H), 6.97 (dd, J = 2.3, 11.2 Hz, 1H), 6.96 (d, J = 8.9 Hz,2H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.53 (s, 1H), 5.10 (s, 2H), 3.85(s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) 385 (M⁺), 341, 247, 138, 121 (base)Example 8-3 Example 1-1

(DMSO-d₆) δ: 9.74 (brs, 1H), 8.21 (s, 1H), 7.75-7.73 (m, 3H), 7.59 (d, J= 8.1 Hz, 1H), 7.40- 7.35 (m, 3H), 7.30- 7.26 (m, 1H), 6.57 (s, 1H),5.29 (s, 2H), 3.85 (s, 3H), 3.69 (s, 3H) 361 (M⁺), 317, 199 (base), 145Example 8-4 Example 1-1

(DMSO-d₆) δ: 9.72 (brs, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.51-7.48 (m, 1H), 7.36 (dd, J = 1.2, 8.5 Hz, 1H),7.25-7.19 (m, 3H), 6.38 (s, 1H), 5.29 (s, 2H), 3.85 (s, 3H), 3.70 (s,3H), 2.43 (s, 3H) 375 (M⁺), 311, 213 (base) Example 8-20 Example 1-1

(DMSO-d₆) δ: 9.64 (brs, 1H), 8.20 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H),7.55 (d, J = 8.9 Hz, 2H), 7.36 (dd, J = 1.2, 8.5 Hz, 1H), 6.72 (d, J =8.9 Hz, 1H), 6.39 (s, 1H), 5.28 (s, 2H), 3.85 (s, 3H), 3.64 (s, 3H),2.91 (s, 6H) 404 (M⁺), 242 (base) Example 8-1 Example 1-1

(DMSO-d₆) δ: 9.85 (brs, 1H), 8.26 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H),7.74 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.46(dd, J = 2.3, 8.5 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 6.67 (s, 1H), 5.30(s, 2H), 3.86 (s, 3H), 3.73 (s, 3H) 267, 162, 145, 133 (base)

TABLE 68 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-5 Example 1-1

(DMSO-d₆) δ: 9.78 (brs, 1H), 8.20 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.46(dd, J = 2.3, 8.5 Hz, 1H), 7.36 (dd, J = 1.2, 8.5 Hz, 1H), 6.67 (s, 1H),5.29 (s, 2H), 4.07 (q, J = 7.3 Hz, 2H), 3.85 (s, 3H), 1.31 (t, J = 7.3Hz, 3H) 399 (M⁺ − 44), 281, 253 (base), 161, 145 Example 8-1 Example 1-2

(DMSO-d₆) δ: 9.83 (brs, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H),7.74 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.46(dd, J = 2.3, 8.5 Hz, 1H), 7.35 (dd, J = 1.2, 8.5 Hz, 1H), 6.66 (s, 1H),5.29 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 3.73 (s, 3H), 1.42 (t, J = 7.3Hz, 3H) 267, 176, 147 (base), 119 Example 8-5 Example 1-2

(DMSO-d₆) δ: 9.77 (brs, 1H), 8.27 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.46(dd, J = 1.9, 8.5 Hz, 1H), 7.34 (dd, J = 1.2, 8.5 Hz, 1H), 6.67 (s, 1H),5.29 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 1.42(t, J = 7.3 Hz, 3H), 1.31 (t, J = 7.3 Hz, 3H) 413 (M⁺ − 44), 281, 253(base), 176, 147 Example 8-6 Example 1-1

(DMSO-d₆) δ: 8.20 (s, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.75 (dd, J = 2.4,8.7 Hz, 1H), 7.74 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.59 (d, J = 8.7Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 6.70 (s, 1H), 5.29 (s, 2H), 4.04 (q,J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H) 281, 253, 161,145, 133 (base) Example 8-19 Example 1-2

(DMSO-d₆) δ: 9.79 (brs, 1H), 8.27 (s, 1H), 7.80 (d, J = 8.1 Hz, 1H),7.73 (s, 1H), 7.71-7.65 (m, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.59-7.55 (m,1H), 7.34 (dd, J = 1.2, 8.1 Hz, 1H), 6.35 (s, 1H), 5.29 (s, 2H), 4.29(q, J = 7.3 Hz, 2H), 3.72 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 399 (M⁺ −44), 267, 176, 159 (base)

TABLE 69 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-7 Example 1-1

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.21 (s, 1H), 7.83 (dd, J = 1.9, 7.7 Hz,1H), 7.73 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H),7.29- 7.25 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.98-6.94 (m, 1H), 6.59(s, 1H), 5.29 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.68 (s, 3H) 391(M⁺), 347, 229 (base), 162 Example 8-32 Example 1-1

(DMSO-d₆) δ: 9.58 (brs, 1H), 8.20 (s, 1H), 7.84 (dd, J = 1.5, 7.7 Hz,1H), 7.73 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.35 (dd, J = 0.8, 8.9 Hz,1H), 7.30- 7.25 (m, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.96 (dt, J = 0.8,7.3 Hz, 1H), 6.58 (s, 1H), 5.28 (s, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.85(s, 3H), 3.83 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H) 405 (M⁺), 361, 133(base) Example 8-7 Example 1-2

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.27 (s, 1H), 7.83 (dd, J = 1.5, 7.7 Hz,1H), 7.74 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H),7.29-7.25 (m, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.98-6.94 (m, 1H), 6.59 (s,1H), 5.28 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 3.82 (s, 3H), 3.69 (s, 3H),1.42 (t, J = 7.3 Hz, 3H) 405 (M⁺), 361, 229, 176, 147 (base) Example8-32 Example 1-2

(DMSO-d₆) δ: 9.59 (brs, 1H), 8.27 (s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz,1H), 7.73 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H),7.27 (ddd, J = 1.5, 7.3, 8.5 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 6.96(dt, J = 1.2, 7.3 Hz, 1H), 6.58 (s, 1H), 5.28 (s, 2H), 4.29 (q, J = 7.3Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 1.42 (t, J = 7.3 Hz,3H), 1.30 (t, J = 7.3 Hz, 3H) 419 (M⁺), 375, 243, 147 (base)

TABLE 70 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-33 Example 1-1

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.20 (s, 1H), 7.82 (dd, J = 6.9, 8.5 Hz,1H), 7.73 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H),6.97 (dd, J = 2.3, 11.6 Hz, 1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.54(s, 1H), 5.28 (s, 2H), 3.85 (s, 6 H), 3.68 (s, 3H) 409 (M⁺), 365, 247,162, 145 (base) Example 8-8 Example 1-1

(DMSO-d₆) δ: 9.60 (brs, 1H), 8.20 (s, 1H), 7.84 (dd, J = 7.3, 8.5 Hz,1H), 7.73 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H),6.97 (dd, J = 2.3, 11.6 Hz, 1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.54(s, 1H), 5.28 (s, 2H), 4.02 (q, J = 7.3 Hz, 2H), 3.85 (s, 6H), 1.29 (t,J = 7.3 Hz, 3H) 423 (M⁺), 379, 261, 162, 133 (base) Example 8-33 Example1-2

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.27 (s, 1H), 7.82 (dd, J = 7.3, 8.5 Hz,1H), 7.73 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.34 (dd, J = 1.2, 8.1 Hz,1H), 6.97 (dd, J = 2.3, 11.6 Hz, 1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H),6.54 (s, 1H), 5.28 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 3.68(s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 423 (M⁺), 247, 176, 147 (base) Example8-8 Example 1-2

(DMSO-d₆) δ: 9.59 (brs, 1H), 8.27 (s, 1H), 7.84 (dd, J = 6.9, 8.5 Hz,1H), 7.73 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H),6.97 (dd, J = 2.7, 11.6 Hz, 1H), 6.79 (dt, J = 2.7, 8.5 Hz, 1H), 6.54(s, 1H), 5.27 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 4.02 (q, J = 7.3 Hz,2H), 3.84 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H)437 (M⁺), 393, 261 (base), 176

TABLE 71 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-9 Example 1-1

(DMSO-d₆) δ: 8.21 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.73 (s, 1H), 7.59(d, J = 8.1 Hz, 1H), 7.36 (dd, J = 1.2, 8.5 Hz, 1H), 7.15 (d, J = 1.9Hz, 1H), 7.02 (dd, J = 1.9, 8.5 Hz, 1H), 6.59 (s, 1H), 5.28 (s, 2H),3.86 (s, 3H), 3.85 (s, 3H), 3.69 (s, 3H) 425 (M⁺), 381, 263, 162, 133(base) Example 8-10 Example 1-1

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.21 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.15(d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.5 Hz, 1H), 6.59 (s, 1H), 5.28(s, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 1.29 (t,J = 7.3 Hz, 3H) 439 (M⁺), 395, 277, 162, 145 (base) Example 8-9 Example1-2

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.27 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 6.9 Hz, 1H), 7.14(d, J = 1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.28(s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H), 3.69 (s, 3H), 1.42 (t,J = 7.3 Hz, 3H) 263, 176, 147, 119, 98 (base) Example 8-10 Example 1-2

(DMSO-d₆) δ: 9.61 (brs, 1H), 8.27 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.73 (s, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 7.3 Hz, 1H), 7.15(d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.5 Hz, 1H), 6.58 (s, 1H), 5.28(s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.86 (s,3H), 1.42 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H) 453 (M^(+),)277, 219, 176, 147 (base)

TABLE 72 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-11 Example 1-1

(DMSO-d₆) δ: 10.05 (brs, 1H), 8.19 (s, 1H), 7.68 (d, J = 0.8 Hz, 1H),7.56 (d, J = 8.1 Hz, 1H), 7.31 (dd, J = 1.5, 8.1 Hz, 1H), 7.26 (d, J =8.1 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.11 (dd, J = 1.9, 8.1 Hz, 1H),6.21 (s, 1H), 5.23 (s, 2H), 4.04-3.97 (m, 1H), 3.84 (s, 3H), 3.81 (s,3H) 1.26 (d, J = 6.5 Hz, 6H) 453 (M⁺), 409, 276, 145 (base) Example 8-34Example 1-1

(DMSO-d₆) δ: 9.61 (brs, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.71 (d, J =7.7 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 6.88(s, 1H), 6.77 (d, J = 7.3 Hz, 1H), 6.54 (s, 1H), 5.28 (s, 2H), 3.85 (s,3H), 3.81 (s, 3H), 3.67 (s, 3H), 2.32 (s, 3H) 405 (M⁺), 361, 243 (base)Example 8-12 Example 1-1

(DMSO-d₆) δ: 9.57 (brs, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.35 (d, J = 8.1 Hz, 1H), 6.89(s, 1H), 6.78 (d, J = 8.1 Hz, 1H), 6.53 (s, 1H), 5.28 (s, 2H), 4.01 (q,J = 7.3 Hz, 2H), 3.85 (s, 3H), 3.81 (s, 3H), 2.32 (s, 3H), 1.29 (t, J =7.3 Hz, 3H) 257, 228, 199, 162, 133 (base) Example 8-34 Example 1-2

(DMSO-d₆) δ: 9.62 (brs, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 0.8, 8.1 Hz, 1H),6.89 (s, 1H), 6.54 (s, 1H), 5.27 (s, 2H), 4.29 (q, J = 7.3 Hz, 2H), 3.81(s, 3H), 3.67 (s, 3H), 2.32 (s, 3H), 1.41 (t, J = 7.3 Hz) 419 (M⁺), 375,243 (base)

TABLE 73 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-12 Example 1-2

(DMSO-d₆) δ: 9.56 (brs, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 6.89(s, 1H), 6.78 (d, J = 7.7 Hz, 1H), 6.53 (s, 1H), 5.27 (s, 2H), 4.29 (q,J = 7.3 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.81 (s, 3H), 2.32 (s, 3H),1.42 (t, J = 7.3 Hz, 3H), 1.29 (t, J = 7.3 Hz, 3H) 433 (M⁺), 389, 257(base), 176 Example 8-13 Example 1-1

(DMSO-d₆) δ: 9.61 (brs, 1H), 8.20 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 6.61(d, J = 2.3 Hz, 1H), 6.56 (dd, J = 2.3, 8.5 Hz, 1H), 6.49 (s, 1H), 5.28(s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.66 (s, 3H) 421(M⁺), 377, 259 (base), 162 Example 8-14 Example 1-1

(DMSO-d₆) δ: 8.21 (s, 1H), 7.73 (s, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36(dd, J = 0.8, 8.1 Hz, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.25 (dd, J = 1.5,8.1 Hz, 1H), 6.95 (d, J = 8.5 Hz, 1H), 6.51 (s, 1H), 5.29 (s, 2H), 3.85(s, 3H), 3.80 (s, 3H), 3.77 (s, 3H), 3.67 (s, 3H) 421 (M⁺), 259 (base)Example 8-15 Example 1-1

(DMSO-d₆) δ: 9.57 (brs, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7.59 (d, J =8.1 Hz, 1H), 7.35 (dd, J = 1.2, 8.5 Hz, 1H), 7.28 (t, J = 8.1 Hz, 1H),6.67 (d, J = 8.5 Hz, 1H), 5.98 (s, 1H), 5.28 (s, 2H), 3.85 (s, 3H), 3.65(s, 6H), 3.64 (s, 3H) 421 (M⁺), 259, 133 (base) Example 8-16 Example 1-1

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.59 (d, J =8.1 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.36 (dd, J = 0.8, 8.5 Hz, 1H),7.04 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 5.29 (s, 2H), 3.85(s, 3H), 3.69 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H) 389 (M⁺), 345, 227(base)

TABLE 74 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-17 Example 1-1

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.05(s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.28 (s, 2H), 4.03 (q,J = 7.3 Hz, 2H), 3.85 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.30 (t, J =7.3 Hz, 3H) 403 (M⁺), 359, 241 (base) Example 8-16 Example 1-2

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.34 (dd, J = 1.2, 8.5 Hz, 1H),7.04 (s, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 5.28 (s, 2H), 4.29(q, J = 7.3 Hz, 2H), 3.69 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H), 1.42 (t,J = 7.3 Hz, 3H) 227, 176 147 (base), 119 Example 8-17 Example 1-2

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.63 (d, J =8.5 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.05(s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.28 (s, 2H), 4.29 (q,J = 7.3 Hz, 2H), 4.02 (q, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H),1.42 (t, J = 7.3 Hz, 3H), 1.30 (t, J = 7.3 Hz, 3H) 417 (M⁺), 373, 241(base), 176 Example 8-6 Example 2-1

(DMSO-d₆) δ: 9.73 (brs, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.75 (dd, J =2.3, 8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J =8.1 Hz, 1H), 7.27 (dd, J = 1.2, 8.1 Hz, 1H), 6.70 (s, 1H), 5.26 (s, 2H),4.04 (q, J = 6.9 Hz, 2H), 3.73 (s, 3H), 2.53 (s, 3H), 1.30 (t, J = 6.9Hz, 3H) none Example 8-4 Example 2-1

(DMSO-d₆) δ: 9.72 (brs, 1H), 7.60 (s, 1H), 7.51-7.49 (m, 1H), 7.49 (d, J= 8.5 Hz, 1H), 7.27 (dd, J = 1.2, 8.5 Hz, 1H), 7.25-7.18 (m, 3H), 6.37(s, 1H), 5.26 (s, 3H), 3.74 (s, 3H), 3.70 (s, 3H), 2.53 (s, 3H), 2.43(s, 3H) 389 (M⁺), 345, 213 (base)

TABLE 75 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-9 Example 2-1

(DMSO-d₆) δ: 9.68 (brs, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.59 (s, 1H),7.49 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 1.2, 8.5 Hz, 1H), 7.14 (d, J =1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H),3.87 (s, 3H), 3.73 (s, 3H), 3.68 (s, 3H), 2.53 (s, 3H) 263, 233, 176(base), 147 Example 8-17 Example 2-1

(DMSO-d₆) δ: 9.64 (brs, 1H), 7.59 (s, 1H), 7.48 (d, J = 8.5 Hz, 1H),7.40 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 7.05 (s, 1H), 7.01(d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 5.25 (s, 2H), 4.04 (q, J = 7.3 Hz,2H), 3.73 (s, 3H), 2.53 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.30 (t, J= 7.3 Hz, 3H) 417 (M⁺), 373, 241 (base), 176, 147 Example 8-1 Example2-2

(DMSO-d₆) δ: 9.82 (brs, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.66 (d, J = 2.3Hz, 1H), 7.63 (s, 1H), 7.51 (s, 1H), 7.48 (d, J = 8.1 Hz, 1H), 7.46 (dd,J = 2.3, 8.5 Hz, 1H), 6.66 (s, 1H), 5.27 (s, 2H), 3.74 (s, 3H), 3.72 (s,3H), 2.88 (q, J = 7.7 Hz, 2H), 1.32 (t, J = 7.7 Hz, 3H) 267 (base), 190,173, 161 Example 8-9 Example 2-2

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H),7.50 (d, J = 8.1 Hz, 1H), 7.27 (dd, J = 1.2, 8.5 Hz, 1H), 7.14 (d, J =2.3 Hz, 1H), 7.02 (dd, J = 2.3, 8.5 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H),3.86 (s, 3H), 3.74 (s, 3H), 3.68 (s, 3H), 2.89 (q, J = 7.7 Hz, 2H), 1.33(t, J = 7.7 Hz, 3H) 263, 234, 189 (base), 173, 161 Example 8-7 Example3-6

(DMSO-d₆) δ: 9.66 (brs, 1H), 7.83 (dd, J = 1.9, 7.7 Hz, 1H), 7.68 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.25-7.29 (m,1H), 7.07 (d, J = 7.7 Hz, 1H), 6.96 (dt, J = 1.2, 7.7 Hz, 1H), 6.58 (s,1H), 5.28 (s, 2H), 4.96 (s, 2H), 4.22-4.15 (m, 4H), 3.83 (s, 3H), 3.68(s, 3H) 229, 204, 187, 175 (base)

TABLE 76 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-32 Example 3-6

(DMSO-d₆) δ: 9.59 (brs, 1H), 7.85 (dd, J = 1.5, 7.7 Hz, 1H), 7.68 (s,1H), 7.55 (d, J = 8.5 Hz, 1H), 7.33-7.28 (m, 1H) 7.27- 7.25 (m, 1H),7.07 (d, J = 8.1 Hz, 1H), 6.96 (dt, J = 1.2, 7.7 Hz, 1H), 6.58 (s, 1H),5.28 (s, 2H), 4.96 (s, 2H), 4.21- 4.15 (m, 4H), 4.03 (q, J = 7.3 Hz,2H), 3.83 (s, 3H), 1.30 (t, J = 7.3 Hz, 3H) 447 (M⁺), 403, 243 (base)Example 8-33 Example 3-6

(DMSO-d₆) δ: 9.66 (brs, 1H), 7.82 (dd, J = 7.3, 8.5 Hz, 1H), 7.68 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 0.8, 8.1 Hz, 1H) 6.97 (dd J= 2.3, 11.6 Hz, 1H), 6.78 (dt, J = 2.3, 8.5 Hz, 1H), 6.54 (s, 1H), 5.28(s, 2H), 4.96 (s, 2H), 4.22- 4.15 (m, 4H), 3.84 (s, 3H), 3.67 (s, 3H)451 (M⁺), 407, 247, 204 (base) Example 8-8 Example 3-6

(DMSO-d₆) δ: 9.62 (brs, 1H), 7.84 (dd, J = 6.9, 8.5 Hz, 1H), 7.68 (s,1H), 7.55 (d, J = 8.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 6.97 (dd, J =2.3, 11.7 Hz, 1H), 6.79 (dt, J = 2.7, 8.5 Hz, 1H), 6.54 (s, 1H), 5.28(s, 2H), 4.97 (s, 2H), 4.23-4.16 (m, 4H), 4.02 (q, J = 7.3 Hz, 2H), 3.85(s, 3H), 1.29 (t, J = 7.3 Hz, 3H) 465 (M⁺), 421, 261 (base) Example 8-9Example 3-6

(DMSO-d₆) δ: 9.68 (brs, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.68 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 1.9 Hz,1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.28 (s, 2H), 4.96(s, 2H), 4.22-4.15 (m, 4H), 3.86 (s, 3H), 3.68 (s, 3H) 467 (M⁺), 449,263, 234, 204 (base), 175 Example 8-10 Example 3-6

(DMSO-d₆) δ: 9.62 (brs, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.67 (s, 1H),7.55 (d, J = 8.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.14 (d, J = 1.9 Hz,1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.28 (s, 2H), 4.96(s, 2H), 4.21-4.17 (m, 4H), 4.03 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 1.29(t, J = 7.3 Hz, 3H) 481 (M⁺), 437, 277, 204, 187 (base)

TABLE 77 Car- boxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-34 Example 3-6 Example 9-249  

(DMSO-d₆) δ: 9.63 (br s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.69 (d, J = 7.7Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.88 (s,1H), 6.77 (d, J = 7.7 Hz, 1H), 6.54 (s, 1H), 5.28 (s, 2H), 4.96 (s, 2H),4.22- 4.15 (m, 4H), 3.81 (s, 3H), 3.66 (s, 3H), 2.32 (s, 3H) 447 (M⁺),403, 243 (base), 204 Example 8-12 Example 3-6 Example 9-250  

(DMSO-d₆) δ: 9.58 (br s, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.67 (s, 1H),7.54 (d, J = 8.1Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 6.89 (s, 1H), 6.78(dd, J = 0.8, 7.7 Hz, 1H), 6.53 (s, 1H), 5.27 (s, 2H), 4.96 (s, 2H),4.22-4.15 (m, 4H), 4.01 (q, J = 7.3 Hz, 2H), 3.82 (s, 3H), 2.32 (s, 3H),1.29 (t, J = 7.3 Hz, 3H) 461 (M⁺), 417, 257 (base) Example 8-16 Example3-6 Example 9-251  

(DMSO-d₆) δ: 9.71 (br s, 1H), 7.68 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H),7.39 (d, J = 8.1 Hz, 1H), 7.32 (dd, J = 1.2, 8.1 Hz, 1H), 7.04 (s, 1H),7.01 (d, J = 7.7 Hz, 1H), 6.33 (s, 1H), 5.28 (s, 2H), 4.96 (s, 2H),4.21-4.16 (m, 4H), 3.68 (s, 3H), 2.39 (s, 3H), 2.28 (s, 3H) 227 (base),204, 187, 175 Example 8-17 Example 3-6 Example 9-252  

(DMSO-d₆) δ: 9.65 (br s, 1H), 7.67 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H),7.41 (d, J = 7.7 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 7.05 (s, 1H), 7.01(d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 5.28 (s, 2H), 4.96 (s, 2H), 4.22-4.15(m, 4H), 4.02 (q, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.30 (t,J = 7.3 Hz, 3H) 241 (base) Example 8-31 Example 3-6 Example 9-253  

(DMSO-d₆) δ: 9.74 (br s, 1H), 7.67 (s, 1H), 7.55-7.50 (m, 2H), 7.32 (d,J = 8.5 Hz, 1H), 7.09 (dd, J = 2.7, 10.0 Hz, 1H), 7.05-7.00 (m, 1H),6.36 (s, 1H), 5.29 (s, 2H), 4.96 (s, 2H), 4.20- 4.15 (m, 4H), 3.69 (s,3H), 2.43 (s, 3H) 435 (M⁺), 231, 204 175 (base)

TABLE 78 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-7 Example 3-2 Example 9-254  

(DMSO-d₆) δ: 9.65 (br s, 1H), 7.84- 7.82 (m, 1H), 7.63 (s, 1H), 7.45 (d,J = 8.5 Hz, 1H), 7.29-7.23 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.98-6.94(m, 1H), 6.58 (s, 1H), 5.26 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 3.83 (s,3H), 3.68 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 2.64 (quint, J = 7.3 Hz,2H) 417 (M⁺), 373, 229, 188, 171 (base) Example 8-32 Example 3-2 Example9-255  

(DMSO-d₆) δ: 9.61 (br s, 1H), 7.86 (dd, J = 1.9, 7.7 Hz, 1H), 7.62 (s,1H), 7.45 (d, J = 8.1 Hz, 1H), 7.28-7.23 (m, 2H), 7.07 (d, J = 7.7 Hz,1H), 6.98-6.94 (m, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.12 (t, J = 6.9 Hz,2H), 4.03 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H),2.64 (t, J = 6.9 Hz, 2H), 1.30 (t, J = 7.3 Hz, 3H) 431 (M⁺), 387, 243,217, 188, 171 (base) Example 8-33 Example 3-2 Example 9-256  

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.82 (dd, J = 7.3, 8.5 Hz, 1H), 7.62 (s,1H), 7.45 (d, J = 8.5 Hz, 1H), 7.24 (dd, J = 1.2, 8.1 Hz, 1H), 6.97 (dd,J = 2.7, 11.6 Hz, 1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.54 (s, 1H),5.25 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 3.84 (s, 3H), 3.67 (s, 3H), 2.96(t, J = 7.3 Hz, 2H), 2.68-2.60 (m, 2H) 435 (M⁺), 391, 247, 171 (base)Example 8-8 Example 3-2 Example 9-257  

(DMSO-d₆) δ: 9.59 (br s, 1H), 7.84 (dd, J = 7.3, 8.5 Hz, 1H), 7.61 (s,1H), 7.45 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 6.96 (dd, J =2.3, 11.5 Hz, 1H), 6.81-6.76 (m, 1H), 6.54 (s, 1H), 5.24 (s, 2H), 4.12(t, J = 6.9 Hz, 2H), 4.03 (t, J = 7.3 Hz, 2H), 3.85 (s, 3H), 2.97 (t, J= 7.3 Hz, 2H), 2.65 (quint, J = 7.3 Hz, 2H), 1.29 (t, J = 7.3 Hz, 3H)449 (M⁺), 405, 261, 188, 171 (base) Example 8-9 Example 3-2 Example9-258  

(DMSO-d₆) δ: 9.68 (br s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.63 (s, 1H),7.45 (d, J = 8.1 Hz, 1H), 7.25 (dd, J = 0.8, 8.1 Hz, 1H), 7.14 (d, J =1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H),4.12 (t, J = 6.9 Hz, 2H), 3.87 (s, 3H), 3.68 (s, 3H), 2.96 (t, J = 6.9Hz, 2H), 2.68-2.60 (m, 2H) 451 (M⁺), 407, 263, 188, 93 (base)

TABLE 79 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-10 Example 3-2 Example 9-259  

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.62 (s, 1H),7.45 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.9 Hz,1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.25 (s, 2H), 4.12(t, J = 6.9 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 2.97 (dt, J= 7.3, 8.1 Hz, 2H), 2.64 (quint, J = 7.3 Hz, 2H), 1.30 (t, J = 7.3 Hz,3H) 465 (M⁺), 421, 277, 188, 171 (base) Example 8-16 Example 3-2 Example9-260  

(DMSO-d₆) δ: 9.71 (br s, 1H), 7.62 (s, 1H), 7.45 (d, J = 8.1 Hz, 1H),7.39 (d, J = 7.7 Hz, 1H), 7.24 (dd, J = 0.8, 8.1 Hz, 1H), 7.04 (s, 1H),7.00 (d, J = 8.1 Hz, 1H), 6.32 (s, 1H), 5.26 (s, 2H), 4.11 (t, J = 7.3Hz, 2H), 3.68 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 2.64 (quint, J = 7.3Hz, 2H), 2.39 (s, 3H), 2.28 (s, 3H) 415 (M⁺), 371, 227, 188, 171 (base)Example 8-34 Example 3-2 Example 9-261  

(DMSO-d₆) δ: 7.70 (d, J = 8.1 Hz, 1H), 7.62 (s, 1H), 7.45 (d, J = 8.1Hz, 1H), 7.24 (dd, J = 1.2, 8.1 Hz, 1H), 6.89 (s, 1H), 6.77 (d, J = 7.3Hz, 1H), 6.53 (s, 1H), 5.25 (s, 2H), 4.12 (t, J = 7.3 Hz, 2H), 3.81 (s,3H), 3.86 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H), 2.68-2.62 (m, 2H), 2.32 (s,3H) 387 (M⁺ − 44), 159 (base) Example 8-12 Example 3-2 Example 9-262  

(DMSO-d₆) δ: 9.56 (br s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (s, 1H),7.45 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 6.89 (s, 1H), 6.78(d, J = 7.3 Hz, 1H), 6.53 (s, 1H), 5.25 (s, 2H), 4.12 (t, J = 6.9 Hz,2H), 4.01 (q, J = 7.3 Hz, 2H), 3.82 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H),2.68-2.60 (m, 2H), 2.32 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H) 445 (M⁺), 401,257, 188, 171 (base) Example 8-7 — Example 9-263  

(DMSO-d₆) δ: 9.63 (br s, 1H), 7.83 (dd, J = 1.5, 7.7 Hz, 1H), 7.60 (s,1H), 7.46 (d, J = 8.5 Hz, 1H), 7.29-7.25 (m, 2H), 7.07 (d, J = 7.7 Hz,1H), 6.96 (dt, J = 0.8, 7.7 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H), 4.10(t, J = 6.2 Hz, 2H), 3.83 (s, 3H), 3.68 (s, 3H), 2.96 (t, J = 6.6 Hz,2H), 2.08-2.02 (m, 2H), 1.96-1.91 (m, 2H) 431 (M⁺), 387, 229, 202, 173(base)

TABLE 80 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-32 — Example 9-264  

(DMSO-d₆) δ: 9.60 (br s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz, 1H), 7.60 (s,1H), 7.46 (d, J = 8.1 Hz, 1H), 7.30-7.23 (m, 2H), 7.07 (d, J = 8.5 Hz,1H), 6.98-6.94 (m, 1H), 6.58 (s, 1H), 5.26 (s, 2H), 4.10 (t, J = 6.2 Hz,2H), 4.02 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 2.98-2.95 (m, 2H),2.08-1.99 (m, 2H), 1.97-1.91 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H) 243, 202173 (base) Example 8-33 — Example 9-265  

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.82 (dd, J = 7.3, 8.9 Hz, 1H), 7.60 (s,1H), 7.46 (d, J = 8.1 Hz, 1H), 7.26 (dd, J = 1.2, 8.5 Hz, 1H), 6.97 (dd,J = 2.3, 11.2 Hz, 1H), 6.79 (dt, J = 2.7, 8.5 Hz, 1H), 6.54 (s, 1H),5.26 (s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.85 (s, 3H), 3.67 (s, 3H), 2.94(t, J = 6.6 Hz, 2H), 2.08-2.02 (m, 2H), 1.96-1.91 (m, 2H) 247 (base),202, 173 Example 8-8 — Example 9-266  

(DMSO-d₆) δ: 9.58 (br s, 1H), 7.84 (dd, J = 7.3, 8.9 Hz, 1H), 7.60 (s,1H), 7.46 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.5 Hz, 1H), 6.97 (dd, J =2.3, 11.6 Hz, 1H), 6.79 (dt, J = 2.7, 8.5 Hz, 1H), 6.53 (s, 1H), 5.26(s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 4.02 (q, J = 7.3 Hz, 2H), 3.85 (s,3H), 2.98-2.95 (m, 2H), 2.08-1.99 (m, 2H), 1.97-1.91 (m, 2H), 1.29 (t, J= 7.3 Hz, 3H) 463 (M⁺), 419, 261 (base) Example 8-9 — Example 9-267  

(DMSO-d₆) δ: 9.65 (br s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H),7.46 (d, J = 8.1 Hz, 1H), 7.25 (dd, J = 1.2, 8.1 Hz, 1H), 7.14 (d, J =1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H),4.10 (t, J = 6.2 Hz, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 2.96 (t, J = 6.6Hz, 2H), 2.08-2.02 (m, 2H), 1.96-1.91 (m, 2H) 263, 173 (base) Example8-10 — Example 9-268  

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.60 (s, 1H),7.46 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.9 Hz,1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H), 4.10(t, J = 6.2 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 2.96 (t, J= 6.6 Hz, 2H), 2.08-2.00 (m, 2H), 1.97-1.90 (m, 2H), 1.29 (t, J = 7.3Hz, 3H) 479 (M⁺), 435, 277, 202 (base)

TABLE 81 Carboxylic Hydroxy Acid compound Example ¹H-NMR Mass, m/zExample 8-34 — Example 9-269  

(DMSO-d₆) δ: 9.60 (br s, 1H), 7.70 (d, J = 7.7 Hz, 1H), 7.60 (s, 1H),7.46 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.24- 7.17 (m, 1H),6.89 (s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 5.26 (s, 2H), 4.10 (t, J = 5.8Hz, 2H), 3.81 (s, 3H), 3.66 (s, 3H), 2.97 (t, J = 6.3 Hz, 2H), 2.32 (s,3H), 2.07-2.04 (m, 2H), 1.97-1.92 (m, 2H) 401 (M⁺ − 44), 173 (base)Example 8-12 — Example 9-270  

(DMSO-d₆) δ: 9.57 (br s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H),7.51 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.78(d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 5.26 (s, 2H), 4.12 (t, J = 6.2 Hz,2H), 4.01 (q, J = 7.3 Hz, 2H), 3.81 (s, 3H), 2.99 (t, J = 6.6 Hz, 2H),2.32 (s, 3H), 2.09-1.99 (m, 2H), 1.97-1.91 (m, 2H), 1.29 (t, J = 7.3 Hz,3H) 459 (M⁺), 415, 257 (base) Example 8-16 — Example 9-271  

(DMSO-d₆) δ: 9.70 (br s, 1H), 7.60 (s, 1H), 7.46 (d, J = 8.1 Hz, 1H),7.49 (d, J = 7.7 Hz, 1H), 7.26 (dd, J = 0.8, 8.1 Hz, 1H), 7.05 (s, 1H),7.01 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 5.27 (s, 2H), 4.10 (t, J = 6.2Hz, 2H), 3.68 (s, 3H), 2.96 (t, J = 6.6 Hz, 2H), 2.39 (s, 3H), 2.28 (s,3H), 2.08- 2.02 (m, 2H), 1.97- 1.91 (m, 2H) 229, 173 (base) Example 8-17— Example 9-272  

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.60 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H),7.40 (d, J = 7.7 Hz, 1H), 7.27-7.24 (m, 1H), 7.05 (s, 1H), 7.01 (d, J =8.1 Hz, 1H), 6.33 (s, 1H), 5.26 (s, 2H), 4.10 (t, J = 6.2 Hz, 2H), 4.02(q, J = 7.3 Hz, 2H), 2.98-2.95 (m, 2H), 2.40 (s, 3H), 2.28 (s, 3H),2.08- 1.99 (m, 2H), 1.96- 1.90 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H) 241(base) Example 8-9 Example 1-6 Example 9-273  

(DMSO-d₆) δ: 9.68 (br s, 1H), 8.20 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H),7.73 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.33 (dd, J = 0.8, 8.5 Hz, 1H),7.14 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.58 (s, 1H),5.28 (s, 2H) 4.42 (t, J = 5.4 Hz, 2H), 3.82 (s, 3H), 3.69 (m, 5H), 3.22(s, 3H) 469 (M⁺), 425, 263, 206, 161 (base)

TABLE 82 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-9 Example 2-4 Example 9-274  

(DMSO-d₆) δ: 9.69 (br s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H),7.58 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 1.5, 8.5 Hz, 1H), 7.14 (d, J =1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.5 Hz, 1H), 6.58 (s, 1H), 5.28 (s, 2H),4.70 (s, 2H), 3.86 (s, 3H), 3.82 (s, 3H), 3.69 (s, 3H), 3.33 (s, 3H) 425(M⁺ − 44), 263, 176 (base) Example 8-1 Example 4-1 Example 9-275  

(DMSO-d₆) δ: 9.84 (br s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.84 (s, 1H),7.80 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 2.3 Hz,1H), 7.48 (dd, J = 1.5, 7.7 Hz, 1H), 7.46 (dd, J = 2.3, 8.5 Hz, 1H),6.66 (s, 1H), 5.28 (s, 2H), 4.03 (s, 3H), 3.72 (s, 3H) 385 (M⁺ − 44),267, 162, 145 (base) Example 8-5 Example 4-1 Example 9-276  

(DMSO-d₆) δ: 9.80 (br s, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.82 (d, J =8.5 Hz, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.66 (s, 1H), 7.47 (dd, J = 1.2,8.5 Hz, 1H), 7.46 (dd, J = 2.3, 8.5 Hz, 1H), 6.67 (s, 1H), 5.28 (s, 2H),4.07 (q, J = 7.3 Hz, 2H), 4.05 (s, 3H), 1.31 (t, J = 7.3 Hz, 3H) 443(M⁺), 399, 281, 253, 145 (base) Example 8-4 Example 4-1 Example 9-277  

(DMSO-d₆) δ: 9.73 (br s, 1H), 8.07 (s, 1H), 7.84 (s, 1H), 7.67 (d, J =8.5 Hz, 1H), 7.51-7.47 (m, 2H), 7.25-7.18 (m, 3H), 6.38 (s, 1H), 5.28(s, 2H), 4.06 (s, 3H), 3.70 (s, 3H), 2.43 (s, 3H) 375 (M⁺), 331, 145(base) Example 8-19 Example 4-1 Example 9-278  

(DMSO-d₆) δ: 9.81 (br s, 1H), 8.20 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H),7.73 (s, 1H), 7.71-7.65 (m, 2H), 7.60-7.55 (m, 2H), 7.36 (d, J = 7.3 Hz,1H), 6.35 (s, 1H), 5.29 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H) 385 (M⁺ −44), 267 (base), 162, 145

TABLE 83 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-8 Example 4-1 Example 9-279  

(DMSO-d₆) δ: 9.60 (br s, 1H), 8.07 (s, 1H), 7.86-7.82 (m, 2H), 7.67 (d,J = 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 2.3, 11.6 Hz,1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.54 (s, 1H), 5.27 (s, 2H), 4.06(s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 1.29 (t, J = 7.3 Hz,3H) 423 (M⁺), 379, 261, 162, 145 (base) Example 8-9 Example 4-1 Example9-280  

(DMSO-d₆) δ: 8.07 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.67(d, J = 8.5 Hz, 1H), 7.48 (dd, J = 1.2, 8.9 Hz, 1H), 7.15 (d, J = 1.9Hz, 1H), 7.02 (dd, J = 1.9, 8.5 Hz, 1H), 6.58 (s, 1H), 5.27 (s, 2H),4.06 (s, 3H), 3.86 (s, 3H), 3.69 (s, 3H) 425 (M⁺), 381, 263, 145 (base)Example 8-10 Example 4-1 Example 9-281  

(DMSO-d₆) δ: 9.67 (br s, 1H), 8.08 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.83 (s, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.15(d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.5 Hz, 1H), 6.58 (s, 1H), 5.27(s, 2H), 4.06 (s, 3H), 4.03 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H), 1.29 (t,J = 7.3 Hz, 3H) 439 (M⁺), 395, 277, 162, 145 (base) Example 8-11 Example4-1 Example 9-282  

(DMSO-d₆) δ: 10.05 (br s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.78 (s, 1H),7.65 (d, J = 8.9 Hz, 1H), 7.43 (dd, J = 1.5, 8.5 Hz, 1H), 7.25 (d, J =8.5 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 1.9, 8.1 Hz, 1H),6.21 (s, 1H), 5.22 (s, 2H), 4.04 (s, 3H), 4.04-3.97 (m, 1H), 3.81 (s,3H) 1.26 (d, J = 6.5 Hz, 6H) 453 (M⁺), 409, 276, 145 (base)

TABLE 84 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-34 Example 4-1 Example 9-283  

(DMSO-d₆) δ: 9.62 (br s, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.70 (d, J =8.1 Hz, 1H), 7.67 (d, J = 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 6.89(s, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.54 (s, 1H), 5.27 (s, 2H), 4.05 (s,3H), 3.81 (s, 3H), 3.67 (s, 3H), 2.32 (s, 3H) 405 (M⁺), 387, 361, 243,162, 145 (base) Example 8-12 Example 4-1 Example 9-284  

(DMSO-d₆) δ: 9.57 (br s, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.72 (d, J =7.7 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 6.89(s, 1H), 6.78 (d, J = 8.5 Hz, 1H), 6.53 (s, 1H), 5.27 (s, 2H), 4.05 (s,3H), 4.01 (q, J = 7.3 Hz, 2H), 3.81 (s, 3H), 2.32 (s, 3H), 1.28 (t, J =7.3 Hz, 3H) 419 (M⁺), 375, 257, 145 (base) Example 8-16 Example 4-1Example 9-285  

(DMSO-d₆) δ: 9.72 (br s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.83 (s, 1H),7.67 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 1.2, 8.9 Hz, 1H), 7.39 (d, J =7.7 Hz, 1H), 7.05 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.33 (s, 1H), 5.28(s, 2H), 4.06 (s, 3H), 3.69 (s, 3H), 2.39 (s, 3H), 2.30 (s, 3H) 389(M⁺), 345, 227, 145 (base) Example 8-17 Example 4-1 Example 9-286  

(DMSO-d₆) δ: 9.65 (br s, 1H), 8.07 (d, J = 0.8 Hz, 1H), 7.83 (s, 1H),7.67 (d, J = 8.9 Hz, 1H), 7.47 (dd, J = 1.2, 8.5 Hz, 1H), 7.40 (d, J =7.7 Hz, 1H), 7.05 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.27(s, 2H), 4.06 (s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.28 (s,3H), 1.30 (t, J = 7.3 Hz, 3H) 403 (M⁺), 359, 241, 145 (base)

TABLE 85 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-18 Example 4-1 Example 9-287  

(DMSO-d₆) δ: 10.07 (br s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.79 (s, 1H),7.64 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 1.5, 8.9 Hz, 1H), 7.27-7.18 (m,3H), 7.14 (s, 1H), 7.09-7.05 (m, 2H), 6.91 (d, J = 8.5 Hz, 1H), 6.91 (s,1H), 6.33 (s, 1H), 5.23 (s, 2H), 4.94 (s, 2H), 4.04 (s, 3H), 2.31 (s,3H), 2.04 (s, 3H) 465 (M⁺), 421, 330, 145 (base) Example 8-7 Example 4-2Example 9-288  

(DMSO-d₆) δ: 9.67 (br s, 1H), 8.36 (s, 1H), 7.82 (dd, J = 1.5, 7.7 Hz,1H), 7.76 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.30-7.25 (m, 2H), 7.07 (d,J = 8.5 Hz, 1H), 6.96 (t, J = 7.3 Hz, 1H), 6.59 (s, 1H), 5.22 (s, 2H),4.17 (s, 3H), 3.83 (s, 3H), 3.69 (s, 3H) 391 (M⁺), 373, 347, 229, 162,145 (base) Example 8-32 Example 4-2 Example 9-289  

(DMSO-d₆) δ: 9.62 (br s, 1H), 8.36 (s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz,1H), 7.76 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.30-7.25 (m, 2H), 7.07 (d,J = 7.7 Hz, 1H), 6.97 (dt, J = 0.8, 7.7 Hz, 1H), 6.59 (s, 1H), 5.21 (s,2H), 4.17 (s, 3H), 4.03 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 1.30 (t, J =7.3 Hz, 3H) 405 (M⁺), 361, 243, 162, 145 (base) Example 8-33 Example 4-2Example 9-290  

(DMSO-d₆) δ: 9.69 (br s, 1H), 8.36 (s, 1H), 7.82 (dd, J = 7.3, 8.5 Hz,1H), 7.76 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H),6.97 (dd, J = 2.3, 11.6 Hz, 1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.55(s, 1H), 5.21 (s, 2H), 4.17 (s, 3H), 3.84 (s, 3H), 3.68 (s, 3H) 247,162, 145 (base)

TABLE 86 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-9 Example 4-2 Example 9-291  

(DMSO-d₆) δ: 9.70 (br s, 1H), 8.36 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H),7.76 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),7.14 (d, J = 1.9 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.59 (s, 1H),5.21 (s, 2H), 4.17 (s, 3H), 3.86 (s, 3H), 3.69 (s, 3H) 425 (M⁺), 381,263, 162, 145 (base) Example 8-10 Example 4-2 Example 9-292  

(DMSO-d₆) δ: 9.64 (br s, 1H), 8.36 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.75 (s, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),7.14 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 6.59 (s, 1H),5.21 (s, 2H), 4.30 (q, J = 7.3 Hz, 2H), 4.17 (s, 3H), 3.86 (s, 3H), 1.29(t, J = 7.3 Hz, 3H) 439 (M⁺), 395, 277, 162, 145 (base) Example 8-34Example 4-2 Example 9-293  

(DMSO-d₆) δ: 9.64 (br s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.71 (d, J =7.7 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),6.89 (s, 1H), 6.54 (s, 1H), 5.21 (s, 2H), 4.17 (s, 3H), 3.81 (s, 3H),3.67 (s, 3H), 2.31 (s, 3H) 406 (M⁺), 361, 243, 162, 145 (base) Example8-13 Example 4-2 Example 9-294  

(DMSO-d₆) δ: 9.61 (br s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.73 (d, J =8.5 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 1.5, 8.9 Hz, 1H),6.61 (d, J = 2.3 Hz, 1H), 6.56 (dd, J = 2.3, 8.5 Hz, 1H), 6.49 (s, 1H),5.21 (s, 2H), 4.17 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H), 3.66 (s, 3H) 421(M⁺), 377, 145 (base) Example 8-16 Example 4-2 Example 9-295  

(DMSO-d₆) δ: 9.73 (br s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.61 (d, J =8.9 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 1.5, 8.9 Hz, 1H),7.01 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.22 (s, 2H), 4.17 (s, 3H), 3.69(s, 3H), 1.39 (s, 3H), 2.29 (s, 3H) 389 (M⁺), 345, 145 (base)

TABLE 87 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-17 Example 4-2 Example 9-296  

(DMSO-d₆) δ: 9.67 (br s, 1H), 8.36 (s, 1H), 7.76 (s, 1H), 7.61 (d, J =8.9 Hz, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.29 (dd, J = 1.2, 8.9 Hz, 1H),7.05 (s, 1H), 7.01 (d, J = 8.1 Hz, 1H), 6.34 (s, 1H), 5.21 (s, 2H), 4.17(s, 3H), 4.02 (q, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.30 (t,J = 7.3 Hz, 3H) 403 (M⁺), 385, 359, 241, 162, 145 (base) Example 8-9(1-Methyl- 1H- indazol- 6-yl) methanol Example 9-297  

(DMSO-d₆) δ: 9.75 (br s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.84 (d, J = 8.1Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.21 (d, J = 8.5 Hz,1H), 7.15 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.5 Hz, 1H), 6.60 (s,1H), 5.32 (s, 2H), 4.05 (s, 3H), 3.86 (s, 3H), 3.71 (s, 3H) 425 (M⁺),381, 263, 162, 145 (base) Example 8-9 Example 4-7 Example 9-298  

(CDCl₃) δ: 7.99 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 8.1 Hz,1H), 7.42 (br s, 1H), 7.18-7.15 (m, 2H), 6.98 (dd, J = 1.9, 8.5 Hz, 1H),6.92 (d, J = 1.9 Hz, 1H), 6.83 (s, 1H), 5.36 (s, 2H), 4.43 (br s, 2H),3.85 (s, 3H), 3.77 (s, 3H), 1.49 (br s, 3H) 439 (M⁺), 395, 263, 176, 159(base) Example 8-17 (1-Methyl- 1H- indazol- 6-yl) methanol Example 9-299 

(DMSO-d₆) δ: 9.71 (br s, 1H), 8.05 (d, J = 0.8 Hz, 1H), 7.78 (d, J = 8.1Hz, 1H), 7.69 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 8.1 Hz,1H), 7.05 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.35 (s, 1H), 5.25 (s, 2H),4.05 (s, 3H), 4.03 (q, J = 6.9 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.31(t, J = 7.3 Hz, 3H) 403 (M⁺), 359, 241, 145 (base)

TABLE 88 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-9 Example 4-5 Example 9-300  

(DMSO-d₆) δ: 9.74 (br s, 1H), 8.33 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H),7.72 (d, J = 8.9 Hz, 1H), 7.64 (s, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.08(dd, J = 0.8, 8.5 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.60 (s, 1H),5.25 (s, 2H), 4.17 (s, 3H), 3.86 (s, 3H), 3.70 (s, 3H) 425 (M⁺), 381,263, 162, 145 (base) Example 8-9 Example 4-6 Example 9-301  

(DMSO-d₆) δ: 9.74 (br s, 1H), 8.38 (s, 1H), 7.84 (d, J = 8.5 Hz, 1H),7.72 (d, J = 8.9 Hz, 1H), 7.65 (s, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.08(dd, J = 0.8, 8.5 Hz, 1H), 7.02 (dd, J = 1.9, 8.1 Hz, 1H), 6.60 (s, 1H),5.25 (s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H) 3.70 (s, 3H), 1.51(t, J = 7.3 Hz, 3H) 439 (M⁺), 395, 263, 176, 159 (base) Example 8-10Example 4-6 Example 9-302  

(DMSO-d₆) δ: 9.66 (br s, 1H), 8.38 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H),7.72 (d, J = 8.9 Hz, 1H), 7.65 (s, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.07(d, J = 8.5 Hz, 1H), 7.03 (dd, J = 1.9, 8.5 Hz, 1H), 6.59 (s, 1H), 5.25(s, 2H), 4.46 (q, J = 7.3 Hz, 2H), 4.04 (q, J = 7.3 Hz, 2H), 3.87 (s,3H) 1.51 (t, J = 7.3 Hz, 3H), 1.30 (t, J = 7.3 Hz, 3H) 453 (M⁺), 409,277, 176, 159 (base) Example 8-17 Example 4-5 Example 9-303  

(DMSO-d₆) δ: 9.70 (br s, 1H), 8.33 (s, 1H), 7.72 (d, J = 8.9 Hz, 1H),7.64 (s, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 7.05(s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.35 (s, 1H), 5.25 (s, 2H), 4.17 (s,3H), 4.04 (q, J = 7.3 Hz, 2H), 2.40 (s, 3H), 2.28 (s, 3H), 1.31 (t, J =7.3 Hz, 3H) 403 (M⁺), 359, 241, 145 (base) Example 8-16 Example 4-6Example 9-304  

(CDCl₃) δ: 7.92 (s, 1H), 7.69 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.42(d, J = 7.7 Hz, 1H), 7.09 (d, J = 8.1 Hz, 1H), 7.03 (s, 1H), 7.01 (d, J= 7.7 Hz, 1H), 6.73 (br s, 1H), 6.31 (s, 1H), 5.31 (s, 2H), 4.48 (q, J =7.3 Hz, 2H), 3.76 (s, 3H), 2.41 (s, 3H), 2.32 (s, 3H), 1.63 (t, J = 7.3Hz, 3H) 403 (M⁺), 359, 227, 176, 159 (base)

TABLE 89 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 8-17 Example 4-6 Example 9-305  

(CDCl₃) δ: 7.93 (s, 1H), 7.70 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.43(d, J = 7.7 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 7.03 (s, 1H), 7.01 (d, J= 8.1 Hz, 1H), 6.55 (br s, 1H), 6.32 (s, 1H), 5.31 (s, 2H), 4.48 (q, J =7.3 Hz, 2H), 4.07 (q, J = 7.3 Hz, 2H), 2.42 (s, 3H), 2.31 (s, 3H), 1.63(t, J = 7.3 Hz, 3H), 1.43 (t, J = 7.3 Hz, 3H) 417 (M⁺), 373, 241, 176,159 (base) Example 8-25 Example 1-1 Example 9-306  

(DMSO-d₆) δ: 9.99 (br s, 1H), 8.19 (s, 1H), 7.70 (s, 1H), 7.57 (d, J =8.5 Hz, 1H), 7.53-7.43 (m, 5H), 7.33 (dd, J = 1.2, 8.5 Hz, 1H), 6.43 (s,1H), 5.25 (s, 2H), 3.84 (s, 3H), 3.72 (s, 3H) 361 (M⁺), 317, 199, 145(base) Example 8-2 Example 1-1 Example 9-307  

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.06 (s, 1H), 7.83 (d, J = 0.8 Hz, 1H),7.80 (s, 1H), 7.65 (d, J = 8.9 Hz, 1H), 7.56 (dd, J = 1.9, 8.1 Hz, 1H),7.51 (d, J = 8.1 Hz, 1H), 7.44 (dd, J = 1.5, 8.9 Hz, 1H), 6.39 (s, 1H),5.23 (s, 2H), 4.05 (s, 3H), 3.52 (s, 3H) 417 (M⁺), 385, 267, 241, 145(base) Example 8-26 Example 1-1 Example 9-308  

(DMSO-d₆) δ: 9.92 (br s, 1H), 8.19 (s, 1H), 7.69 (s, 1H), 7.57 (d, J =8.1 Hz, 1H), 7. 32 (dd, J = 1.5, 8.1 Hz, 1H), 7.31 (dd, J = 6.6, 8.5 Hz,1H), 7.08 (dd, J = 2.3, 11.6 Hz, 1H), 6.87 (dt, J = 2.3, 8.5 Hz, 1H),6.26 (s, 1H), 5.24 (s, 2H), 3.84 (s, 3H), 3.82 (s, 3H), 3.47 (s, 3H) 409(M⁺), 365, 247, 162, 147 (base) Example 8-27 Example 1-1 Example 9-309  

(DMSO-d₆) δ: 8.20 (s, 1H), 7.69 (s, 1H), 7. 58 (d, J = 8.5 Hz, 1H), 7.32(d, J = 8.1 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 1.9 Hz, 1H),7.11 (dd, J = 1.9, 8.1 Hz, 1H), 6.29 (s, 1H), 5.23 (s, 2H), 3.84 (s,3H), 3.83 (s, 3H), 3.49 (s, 3H) 425 (M⁺), 381, 263 145 (base)

TABLE 90 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-27 Example 4-1 Example 9-310  

(DMSO-d₆) δ: 9.98 (br s, 1H), 8.06 (s, 1H), 7.79 (s, 1H), 7.65 (d, J =8.9 Hz, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.25(d, J = 1.9 Hz, 1H), 7.11 (dd, J = 1.9, 8.1 Hz, 1H), 6.28 (s, 1H), 5.23(s, 2H), 4.05 (s, 3H), 3.83 (s, 3H), 3.48 (s, 3H) 425 (M⁺), 381, 263,145 (base) Example 8-24 Example 1-1 Example 9-311  

(DMSO-d₆) δ: 9.30 (br s, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.35 (d, J = 5.4 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.15(d, J = 1.5 Hz, 1H), 7.03 (dd, J = 1.5, 8.1 Hz, 1H), 5.27 (s, 3H), 3.85(s, 3H), 3.78 (s, 3H), 3.61 (s, 3H), 1.72 (s, 3H) 277, 144 (base)Example 8-24 Example 2-1 Example 9-312  

(DMSO-d₆) δ: 9.28 (br s, 1H), 7.58 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H),7.27 (s, 1H), 7.25 (s, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9,8.1 Hz, 1H), 5.24 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.61 (s, 3H),2.53 (s, 3H), 1.71 (s, 3H) 453 (M⁺), 409, 159 (base) Example 8-24Example 1-2 Example 9-313  

(DMSO-d₆) δ: 9.30 (br s, 1H), 8.28 (s, 1H), 7.72 (s, 1H), 7.63 (d, J =8.1 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.14(d, J = 1.5 Hz, 1H), 7.03 (dd, J = 1.5, 8.1 Hz, 1H), 5.27 (s, 3H), 4.29(q, J = 7.3 Hz, 2H), 3.78 (s, 3H), 3.62 (s, 3H), 1.72 (s, 3H), 1.42 (t,J = 7.3 Hz, 3H) 453 (M⁺), 159 (base)

TABLE 91 Carboxylic Hydroxy Mass, Acid compound Example ¹H-NMR m/zExample 8-24 Example 4-1 Example 9-314  

(DMSO-d₆) δ: 9.29 (br s, 1H), 8.07(s, 1H), 7.83 (s, 1H), 7.67 (d, J =8.5 Hz, 1H), 7.48 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 2.9Hz, 1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 5.26 (s, 3H), 4. 05 (s, 3H),3.78 (s, 3H), 3.61 (s, 3H), 1.71 (s, 3H) 439 (M⁺), 395, 145 (base)Example 8-28 4-Methoxy benzyl alcohol Example 9-315  

(DMSO-d₆) δ: 12.34 (br s, 1H), 9.88 (br s, 1H), 7.35 (d, J = 8.9 Hz,2H), 7.30 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H),6.94 (d, J = 8.9 Hz, 1H), 6.41 (s, 1H), 5.06 (s, 2H), 3.76 (s, 3H), 2.32(s, 3H), 2.30 (s, 3H) 351 (M⁺), 121 (base) Example 8-29 Example 1-1Example 9-316  

(DMSO-d₆) δ: 12.41 (br s, 1H), 9.92 (br s, 1H), 8.19 (s, 1H), 7.71 (s,1H), 7.65 (d, J = 6.9 Hz, 1H), 7.57 (d, J = 8.5 Hz, 1H), 7.33 (dd, J =1.5, 8.5 Hz, 1H), 7.20 (s, 1H), 7.08 (dd, J = 1.9, 8.1 Hz, 1H), 6.73 (s,1H), 5.25 (s, 2H), 3.90 (s, 3H), 3.84 (s, 3H) 411 (M⁺), 267, 133 (base)Example 8-28 Example 1-1 Example 9-317  

(DMSO-d₆) δ: 12.34 (br s, 1H), 9.92 (br s, 1H), 8.19 (s, 1H), 7.71 (s,1H), 7.57 (d, J = 8.5 Hz, 1H), 7.33 (dd, J = 1.5, 8.5 Hz, 1H), 7.30 (d,J = 7.7 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.43 (s, 1H),5.25 (s, 2H), 3.84 (s, 3H), 2.32 (s, 3H), 2.30 (s, 3H) 375 (M⁺), 331,145 (base) Example 8-23 Example 1-1 Example 9-318  

(DMSO-d₆) δ: 9.80 (br s, 1H), 8.20 (s, 1H), 7.73 (s, 1H), 7.65 (dd, J =0.8, 1.9 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H),6.64 (d, J = 2.7 Hz, 1H), 6.53 (dd, J = 1.5, 3.1 Hz, 1H), 6.39 (s, 1H),5.29 (s, 2H), 3.85 (s, 3H), 3.67 (s, 3H) 351 (M⁺), 307, 189 (base), 162

TABLE 92 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-319 Example 8-22 4-Methoxy benzyl alcohol

(DMSO-d₆) δ :9.70 (brs, 1H), 7.58 (dd, J = 1.5, 7.3Hz, 1H), 7.37 (d, J =8.1Hz, 2H), 7.18 (dt, J = 1.9, 8.1Hz, 1H), 7.00- 6.95 (m, 3H), 6.92(d, J= 8.1Hz, 1H), 5.09 (s, 4H), 4.01 (q, J = 6.9Hz, 2H), 3.77 (s, 3H), 2.32(s, 3H), 1.30 (t, J = 6.9Hz, 3H) 379 (M⁺), 335, 121 (base) Example 9-320Example 8-21 Example 1-1

(DMSO-d₆) δ :9.76 (brs, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 7.59 (d, J =8.5 Hz, 1H), 7.56 (dd, J = 1.2, 7.7Hz, 1H), 7.36 (d, J = 8.1Hz, 1H),7.18 (dt, J = 1.5, 7.7Hz, 1H), 6.97 (dt, J = 0.8, 7.3Hz, 1H), 6.91 (d, J= 8.1 Hz, 1H), 5.28 (s, 2H), 5.11 (brs, 2H), 3.85 (s, 3H), 3.69 (s, 3H)389 (M⁺), 345, 226 (base) Example 9-321 Example 8-22 Example 1-1

(DMSO-d₆) δ :9.70 (brs, 1H), 8.21 (s, 1H), 7.73 (s, 1H), 7.59 (d, J =8.1Hz, 1H), 7.58 (dd, J = 1.5, 7.3Hz, 1H), 7.35 (d, J = 8.1Hz, 1H),7.27-7.24 (m, 1H), 7.00-6.96(m, 1H), 6.92 (d, J = 7.7Hz, 1H), 5.28 (s,2H), 5.09 (brs, 2H), 4.02 (q, J = 7.3 Hz, 2H), 3.85 (s, 3H), 2.31 (s,3H), 1.30 (t, J = 7.3Hz, 3H) 403 (M⁺), 240 (base) Example 9-322 Example8-21 Example 2-1

(DMSO-d₆) δ :9.74 (brs, 1H), 7.60 (s, 1H), 7.56 (d, J = 7.3Hz, 1H), 7.49(d, J = 8.1Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 7.18 (t, J = 7. 3Hz, 1H),6.97 (t, J = 7.3 Hz, 1H), 6.91 (d, J = 8.1Hz, 1H), 5.25 (s, 2H), 5.10(brs, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 2.53 (s, 3H) 403 (M⁺), 226 (base)

TABLE 93 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-323 Example 8-22 Example 2-1

(DMSO-d₆) δ :9.71 (brs, 1H), 7.59 (s, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.49(d, J = 8.1Hz, 1H), 7.26 (d, J = 8.5Hz, 1H), 7.18 (dt, J = 1.5, 7.7Hz,1H), 6.97 (dt, J = 0.8, 7.3hZ, 1H), 6.91 (d, J = 8.1Hz, 1H), 5.25 (s,2H), 5.09 (brs, 2H), 4.02 (q, J = 7.3Hz, 2H), 3.74 (s, 3H), 1.30 (t, J =7.3z, 3H) 417 (M⁺), 240 (base) Example 9-324 Example 8-21 Example 4-1

(DMSO-d₆) δ :9.80 (brs, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.67 (d, J =8.9Hz, 1H), 7.56 (dd, J = 1.5, 7.7Hz, 1H), 7.48 (d, J = 8.5Hz, 1H), 7.18(dt, J = 1.5, 8.1Hz, 1H), 6. 97 (dt, J = 0.8, 7.3Hz, 1H), 6.91 (d, J =7.7Hz, 1H), 5.27 (s, 2H), 5.11 (brs, 2H), 4.06 (s, 3H), 3.69 (s, 3H) 389(M⁺), 345, 145 (base) Example 9-325 Example 8-22 Example 4-1

(DMSO-d₆) δ :9.71 (brs, 1H), 8.07 (s, 1H), 7.83 (s, 1H), 7.67 (d, J =8.5Hz, 1H), 7.58 (dd, J = 1.5, 7.7Hz, 1H), 7.47 (d, J = 8.5Hz, 1H), 7.18(dt, J = 1.5, 7.7Hz, 1H), 6.99-6.96 (m, 1H), 6.92 (d, J = 8.1Hz, 1H),5.27 (s, 2H), 5.10 (brs, 2H), 4.06 (s, 3H), 4.01 (q, J = 7.3Hz, 2H),1.30 (t, J = 7.3Hz, 3H) 403 (M⁺), 359, 145 (base) Example 9-326 Example8-35 Example 1-1

(DMSO-d₆) δ :9.91 (brs, 1H), 8.20 (s, 1H), 7.72 (s, 1H), 7.70 (d, J =7.7Hz, 1H), 7.58 (d, J = 8.1Hz, 1H), 7.50 (s, 1H), 7.37-7.34 (m, 2H), 7.27 (dd, J = 6.9, 7.7Hz, 1H), 5.27 (s, 2 H), 3.95 (s, 3H), 3.84 (s, 3H),3. 63 (brs, 3H) 373 (M⁺), 329, 211 (base)

TABLE 94 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-327 Example 8-35 Example 2-1

(DMSO-d₆) δ :9.89 (brs, 1H), 7.70 (d, J = 7.7Hz, 1H), 7.58 (s, 1H), 7.51(s, 1H), 7.48 (d, J = 8.5Hz, 1H), 7.38-7.34 (m, 1H), 7.29-7.25 (m, 2H),5.24 (s, 2H), 3.95 (s, 3H), 3.73 (s, 3H), 3.63 (brs, 2H), 2.52 (s, 3H)387 (M⁺), 343, 159 (base) Example 9-328 Example 8-35 Example 4-1

(DMSO-d₆) δ :9.92 (brs, 1H), 8.07 (d, J = 0.8Hz, 1H), 7.82 (s, 1H), 7.70(d, J = 7.3 Hz, 1H), 7.66 (d, J = 8.5Hz, 1H), 7.50 (s, 1H), 7.47 (dd, J= 1.2, 8.5Hz, 1H), 7.37-7.34 (m, 1H), 7.29-7.25 (m, 1H), 5.26 (s, 2H),4.05 (s, 3H), 3.95 (s, 3H), 3.63 (brs, 3H) 373 (M⁺), 329, 145 (base)Example 9-329 Example 8-9 4-Fluoro benzyl alcohol

(DMSO-d₆) δ :9.73 (brs, 1H), 7.84 (d, J = 8.1Hz, 1H), 7.51- 7.48 (m,2H), 7.26-7.22 (m, 2H), 7.15 (d, J = 1.9Hz, 1H), 7.02 (dd, J = 1.9,8.1Hz, 1H), 6.58 (s, 1H), 5.16 (s, 2H), 3.87 (s, 3H), 3.69 (s, 3H) 389(M⁺), 263, 236, 126, 109 (base) Example 9-330 5-(4-Chloro phenyl)furan-2-carboxylic acid Example 1-2

(DMSO-d₆) δ :10.47 (brs, 1H), 8.27 (s, 1H), 7.72 (s, 1H), 7.62 (d, J =8.5Hz, 1H), 7.58 (d, J = 8.9Hz, 2H), 7.44 (d, J = 8.9Hz, 2H), 7.33 (dd,J = 1.5, 8.5Hz, 1H), 6.94 (d, J = 3.5Hz, 1H), 6.12 (d, J = 3.1Hz, 1H),5.27 (s, 2H), 4.28 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H) 395(M⁺), 351, 159 (base) Example 9-331 3-(4-Chloro phenyl)-2- methylfuran-3-carboxylic acid Example 1-2

(DMSO-d₆) δ :9.14 (brs, 1H), 8.26 (s, 1H), 7.72 (s, 1H), 7.63 (d, J =8.1Hz, 1H), 7.62 (d, J = 8.1Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.33 (dd,J = 0.8, 8.1Hz, 1H), 7.08 (brs, 1H), 5.24 (s, 2H), 4.28 (q, J = 7.3Hz,2H), 2.27 (s, 3H), 1.41 (t, J = 7.3Hz, 3H) 409 (M⁺), 365, 159 (base)

TABLE 95 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-332 4-(4-Chloro phenyl) thiophene- 2- carboxylic acid Example1-2

(DMSO-d₆) δ :10.82 (brs, 1H), 8.27 (s, 1H), 7.73 (s, 1H), 7.63 (d, J =8.1Hz, 1H), 7.61 (d, J = 8.1Hz, 2H), 7.43 (d, J = 8.1Hz, 2H), 7.35(dd, J= 1.2, 8.5Hz, 1H), 7.30 (d, J = 1.5Hz, 1H), 6.90 (d, J = 1.5Hz, 1H),5.30 (s, 2H), 4.28 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3Hz, 3H) 411(M⁺), 367, 235 (base) Example 9-333 4-(4-Chloro phenyl) thiophene- 2-carboxylic acid —

(DMSO-d₆) δ :10.82 (brs, 1H), 7.62-7.60 (m, 3H), 7.43 (d, J = 8.5Hz,2H), 7.31 (d, J = 1.5Hz, 1H), 7.26 (dd, J = 1.5, 8.5Hz, 1H), 6.89 (d, J= 1.5Hz, 1H), 5.28 (s, 2H), 4.09 (t, J = 6.2Hz, 2H), 2.96 (t, J = 6.2Hz,2H), 2.08-2.02 (m, 2H), 1.96-1.90 (m, 2H) 437 (M⁺), 393, 235 (base)Example 9-334 5-(2,4- Dichloro phenyl)thia diazole- 2- carboxylic acidExample 1-1

(DMSO-d₆) δ :12.47 (brs, 1H), 8.22 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H),7.88 (d, J = 2.3Hz, 1H), 7.76 (s, 1H), 7.61 (dd, J = 2.3, 8.5Hz, 1H),7.60 (d, J = 8.1Hz, 1H), 7.38 (dd, J = 1.5, 8.5Hz, 1H), 5.40 (s, 2H),3.85 (s, 3H) 389 (M⁺ − 44), 133 (base) Example 9-335 5-(2,4- Dichlorophenyl)thia diazole- 2- carboxylic acid Example 4-1

(DMSO-d₆) δ :12.47 (brs, 1H), 8.13 (d, J = 8.5Hz, 1H), 8.09 (d, J =8.5Hz, 1H), 7.89 (d, J = 2.3Hz, 1H), 7.86 (s, 1H), 7.68 (d, J = 8. 9Hz,1H), 7.62 (dd, J = 2.3, 8.5Hz, 1H), 7.49 (dd, J = 1.5, 8.5Hz. 1H), 5.39(s, 2H), 4.06 (s, 3H) 433 (M⁺), 389, 145 (base) Example 9-336 Example7-8 4-Methoxy phenethyl alcohol

(DMSO-d₆) δ :9.90 (brs, 1H), 8.18 (dd, J = 1.5, 7.7Hz, 1H), 7.42-7.37(m, 1H), 7.23-7.19 (m, 2H), 7.12 (dd, J = 1.9, 6.6 Hz, 1H), 7.08-7.04(m, 1H), 6.89 (d, J = 8.1Hz, 1H), 6.85- 6.81 (m, H), 4.30 (t, J = 6.9Hz,2H), 3.98 (s, 3H), 3.72 (s, 3 H), 2.90 (t, J = 6.9Hz, 2H), 2.30 (s, 3H)398 (M⁺), 135 (base)

TABLE 96 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-337 Example 8-5 Example 1-5

(DMSO-d₆) δ :9.76 (brs, 1H), 8.19 (s, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.70(s, 1H), 7.65 (d, J = 2.3Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.46 (dd, J= 2.3, 8.5Hz, 1H), 7.34 (d, J = 8.1Hz, 1 H), 6.64 (s, 1H), 5.95 (q, J =6.6Hz, 1H), 4.06 (q, J = 7.3Hz, 2H), 3.84 (s, 3H), 1.61 (d, J = 6.6Hz,3H), 1.30 (t, J = 7.3Hz, 3H) 457 (M⁺), 158 (base) Example 9-338 Example8-9 Example 1-5

(DMSO-d₆) δ :9.66 (brs, 1H), 8.19 (s, 1H), 7.83 (d, J = 8.5Hz, 1H), 7.70(s, 1H), 7.57 (d, J = 8.5Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.14 (d, J =1.9Hz, 1H), 7.02 (dd, J = 1.9, 8.1Hz, 1 H), 6.56 (s, 1H), 5.95 (q, J =6.6Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 3.68 (s, 3H), 1.61 (d, J =6.6Hz, 3H) 395 (M⁺ − 44), 133 (base) Example 9-339 Example 8-16 Example1-5

(DMSO-d₆) δ :9.69 (brs, 1H), 8.19 (s, 1H), 7.70 (s, 1H), 7.57 (d, J =8.1Hz, 1H), 7.38 (d, J = 7.7Hz, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.04 (s,1H), 7.00 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 5.95 (q, J = 6.6Hz, 1H),3.84 (s, 3H), 3.68 (s, 3H), 2.38 (s, 3H), 2.27 (s, 3H), 1.61 (d, J =6.6Hz, 3H) 403 (M⁺), 359, 158 (base) Example 9-340 — Example 3-7

(DMSO-d₆) δ :10.09 (brs, 1H), 8.17 (d, J = 8.5Hz, 1H), 7.65 (s, 1H),7.47 (d, J = 8.1Hz, 1H), 7.30 (d, J = 1.9Hz, 1H), 7.26 (d, J = 8.1Hz,1H), 7.12 (dd, J = 1.9, 8.5Hz, 1H), 5.64 (d, J = 4.2Hz, 1H), 5.29 (s,2H), 5.01- 4.97 (m, 1H), 4.30 (dd, J = 5.8Hz, 11.2Hz, 1H), 4.02 (s, 3H),3.93 (dd, J = 2.3, 11.3Hz, 1H), 3.29-3.24 (m, 1H), 2.79 (dd, J = 2.7,17.0Hz, 1H), 2.31 (s, 3H) 440 (M⁺ − 44), 254 (base) Example 9-341Example 7-14 Example 3-7

(DMSO-d₆) δ :9.94 (brs, 1H), 8.04 (d, J = 8.1Hz, 1H), 7.64 (s, 1H), 7.47(d, J = 8.5Hz, 1H), 7.26 (d, J = 8.5Hz, 1H), 7.02 (s, 1H), 6.87 (d, J =8.1Hz, 1H), 5.64 (d, J = 4.2Hz, 1H), 5.28 (s, 2H), 5.01-4.97 (m, 1H),4.30 (dd, J = 5.8, 11.2Hz, 1 H), 3.96 (s, 3H), 3.93 (dd, J = 2.7,11.3Hz, 1H), 3.34-3.24 (m, 1H), 2.79 (dd, J = 2.7, 17.0Hz, 1H), 2.35 (s,3H), 2.28 (s, 3H) 420 (M⁺ − 44), 234 (base)

TABLE 97 Car- Hydroxy boxylic com- Mass, acid pound Example ¹H-NMR m/zExample 9-342 Example 7-14 Example 3-8

(DMSO-d₆) δ :9. 94 (brs, 1H), 8.04 (d, J = 7.7Hz, 1H), 7.61 (s, 1H),7.48 (d, J = 8.5Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 7.02 (s, 1H), 6.87 (d,J = 8.1Hz, 1H), 5.28 (s, 2H), 5.17 (d, J = 3.5Hz, 1H), 4.28-4.27 (m,1H), 4.13 (t, J = 6.6Hz, 1H), 3.96 (s, 3H), 3.15 (dd, J = 3.9, 17.0Hz,1H), 2.90 (dd, J = 5.4, 17.0 Hz, 1H), 2.35 (s, 3H), 2.28 (s, 3H),2.19-2.11 (m, 2H) 478 (M⁺), 434, 201 (base) Example 9-343 — Example 3-8

(DMSO-d₆) δ :10.08 (brs, 1H), 7.16 (d, J = 8.5Hz, 1H), 7.62 (s, 1H),7.48 (d, J = 8.1Hz, 1H), 7.30 (d, J = 1.9Hz, 1H), 7.28 (d, J = 8.5Hz,1H), 7.12 (dd, J = 1.9, 8.5Hz, 1H), 5.29 (s, 2 H), 5.18 (d, J = 3.5Hz,1H), 4.29-4.26 (m, 1H), 4.13 (t, J = 6.6Hz, 1H), 4.02 (s, 3H), 3.15 (dd,J = 4.2, 17.0Hz, 1H), 2.90 (dd, J = 5.4, 17.3Hz, 1H), 2.31 (s, 3H),2.19-1.91 (m, 2H) 454 (M⁺ − 44), 254 (base) Example 9-344 Example 7-31Example 1-1

(DMSO-d₆) δ :9.91 (brs, 1H), 8.20 (s, 1H), 8.07 (d, J = 7.7Hz, 1H), 7.74(s, 1H), 7.59 (d, J = 8.1Hz, 1H), 7.36 (d, J = 8.1 Hz, 1H), 7.02 (s,1H), 6.88 (d, J = 8.1Hz, 1H), 5.30 (s, 2H), 3.96 (s, 3H), 3.85 (s, 3H),2.66 (q, J = 7.7Hz, 2H), 2.36 (s, 3H), 1.17 (t, J = 7.7Hz, 3H) 436 (M⁺),392, 274 (base) Example 9-345 Example 7-41 Example 1-2

(DMSO-d₆) δ :10.20 (brs, 1H), 8.27 (s, 1H), 7.75 (s, 1H), 7.70 (d, J =8.5Hz, 1H), 7.63 (d, J = 8.1Hz, 1H), 7.44 (d, J = 2.3Hz, 1H), 7.36 (d, J= 1.9Hz, 1H), 7.34 (d, J = 1.9Hz, 1H), 5.31 (s, 2H), 4.29 (q, J = 7.3Hz, 2H), 2.69 (q, J = 7.3Hz, 2 H), 2.53 (s, 3H), 1.41 (t, J = 7.3Hz,3H), 1.17 (t, J = 7.3Hz, 3H) 454 (M⁺), 410, 278 (base)

TABLE 98 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-346 Example 7-40 Example 1-2

(DMSO-d₆) δ :9.99 (brs, 1H), 8.27 (s, 1H), 8.20 (dd, J = 6.9, 8.9Hz,1H), 7.74 (s, 1H), 7.63 (d, J = 8.5Hz, 1H), 7.35 (d, J = 8.5Hz, 1H),7.13 (dd, J = 2.3, 11.2Hz, 1H), 6.91 (dt, J = 2.7, 8.5Hz, 1H), 5.30 (s,2H), 4.29 (q, J = 7.3Hz, 2H), 4.00 (s, 3H), 2.67 (q, J = 7.3Hz, 2H),1.41 (t, J = 7.3Hz, 3H), 1.17 (t, J = 7.7Hz, 3H) 454 (M⁺), 410 Example9-347 Example 7-27 Example 3-2

(DMSO-d₆) δ :9.97 (brs, 1H), 8.19 (dd, J = 1.9, 8.1Hz, 1H), 7.64 (s,1H), 7.45 (d, J = 8.1Hz, 1H), 7.41-7.37 (m, 1H), 7.25 (d, J = 8.5Hz,1H), 7.20 (d, J = 8.1Hz, 1H), 7.08-7.04(m, 1H), 5.28 (s, 2H), 4.12 (t, J= 6.9Hz, 2H), 3.98 (s, 3H), 2.96 (t, J = 7.3Hz, 2H), 2.71-2.60 (m, 4H),1.18 (t, J = 7.3Hz, 3H) 448 (M⁺), 404 Example 9-348 Example 7-30 Example3-2

(DMSO-d₆) δ :10.15 (brs, 1H), 7.70 (dd, J = 6.9, 8.9Hz, 1 H), 7.63 (s,1H), 7.45 (d, J = 8.1Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 7.21 (dd, J =2.7, 10.0Hz, 1H), 7.12 (dt, J = 2.7, 8.5Hz, 1H), 5.28 (s, 2H), 4.11 (t,J = 6.9Hz, 2H), 2.96(t, J = 7.3 Hz, 2H), 2.71-2.60 (m, 4H), 2.53 (s,3H), 1.18 (t, J = 7.3Hz, 3H) 450 (M⁺), 406, 262 (base) Example 9-349Example 7-41 Example 3-2

(DMSO-d₆) δ :10.21 (brs, 1H), 7.70 (d, J = 8.1Hz, 1H), 7.64 (s, 1H),7.45 (d, J = 8.1Hz, 1H), 7.44 (s, 1H), 7.35 (dd, J = 1.9, 8.1Hz, 1H),7.25 (d, J = 8.5Hz, 1H), 5.29 (s, 2H), 4.11 (t, J = 6. 9Hz, 2H), 2.96(t, J = 7.3Hz, 2H), 2.72-2.60 (m, 4 H), 2.54 (s, 3H), 1.18 (t, J =7.3Hz, 3H) 466 (M⁺), 422 (base)

TABLE 99 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-350 Example 7-29 Example 3-2

(DMSO-d₆) δ :10.10 (brs, 1H), 7.63 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.45 (d, J = 8.1Hz, 1H), 7.25 (d, J = 8.1Hz, 1H), 7.14 (s, 1H), 7.10 (d,J = 8.1Hz, 1H), 5.28 (s, 2H), 4.11 (t, J = 6. 9Hz, 2H), 2.96 (t, J =7.7Hz, 2H), 2.68-2.62 (m, 4H), 2.50 (s, 3H), 2.31 (s, 3H), 1.17 (t, J =7.7Hz, 3H) 446 (M⁺), 402, 258 Example 9-351 Example 7-27 —

(DMSO-d₆) δ :9.97 (brs, 1H), 8.19 (dd, J = 1.5, 8.1Hz, 1H), 7.61 (s,1H), 7.47 (d, J = 8.1Hz, 1H), 7.39 (dt, J = 1.5, 8.5Hz, 1H), 7.27 (d, J= 8.1Hz, 1H), 7.20 (d, J = 8.5Hz, 1H), 7.06 (t, J = 8.1 Hz, 1H), 5.28(s, 2H), 4.10 (t, J = 6.1Hz, 2H), 3.98 (s, 3H), 2.96 (t, J = 6.1 Hz,2H), 2.68 (q, J = 7.3Hz, 2H), 2.10- 2.01 (m, 2H), 1.98-1.89 (m, 2H),1.18 (t, J = 7.3Hz, 3H) 462 (M⁺), 185 (base) Example 9-352 Example 7-40—

(DMSO-d₆) δ :9.98 (brs, 1H), 8.20 (dd, J = 6.9, 8.9Hz, 1H), 7.61 (s,1H), 7.46 (d, J = 8.1Hz, 1H), 7.26 (d, J = 8.5Hz, 1 H), 7.13 (dd, J =2.3, 11.2Hz, 1H), 6.91 (dt, J = 2.3, 8.5Hz, 1H), 5.28 (s, 2H), 4.10 (t,J = 6.2Hz, 2H), 4.00 (s, 3H), 2.96 (t, J = 6.2Hz, 2H), 2.67 (q, J =7.3Hz, 2H), 2.08-2.02 (m, 2 H), 1.96-1.90 (m, 2H), 1.17 (t, J = 7.3Hz,3H) 480 (M⁺), 436, 278 Example 9-353 Example 7-31 —

(DMSO-d₆) δ :9.90 (brs, 1H), 8.06 (d, J = 8.1Hz, 1H), 7.61 (s, 1H), 7.46(d, J = 8.5Hz, 1H), 7.26 (d, J = 8.1Hz, 1H), 7.02 (s, 1H), 6.88 (d, J =8.1Hz, 1H), 5.27 (s, 2H), 4.10 (t, J = 5.1Hz, 2H), 3.96 (s, 3H), 2.96(t, J = 7.2Hz, 2H), 2.64 (q, J = 7.7Hz, 2H), 2.36 (s, 3H), 2.08- 2.02(m, 2H), 1.96-1.90 (m, 2H), 1.17 (t, J = 7.7Hz, 3H) 476 (M⁺), 432, 274(base)

TABLE 100 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-354 Example 7-29 —

(DMSO-d₆) δ :10.06 (brs, 1H), 7.61 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.46 (d, J = 8.1Hz, 1H), 7.26 (d, J = 8.1Hz, 1H), 7.14 (s, 1H), 7.10 (d,J = 7.7Hz, 1H), 5.28 (s, 2H), 4.10 (t, J = 5.8Hz, 2H), 2.96 (t, J =6.2Hz, 2H), 2.67 (q, J = 7.7Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H),2.08-2.02 (m, 2H), 1.96-1.90 (m, 2H), 1.17 (t, J = 7.7Hz, 3H) 460 (M⁺),416, 185 (base) Example 9-355 Example 7-30 —

(DMSO-d₆) δ :10.15(brs, 1H), 7.70 (dd, J = 6.2, 8.9Hz, 1 H), 6.15 (s,1H), 7.46 (d, J = 8.1Hz, 1H), 7.26 (d, J = 7.3Hz, 1H), 7.21 (dd, J =2.7, 10.4Hz, 1H), 7.12 (dt, J = 2.7, 8.5Hz, 1H), 5.29 (s, 2H), 4.10 (t,J = 5.8Hz, 2H), 2.96 (t, J = 6.2 Hz, 2H), 2.68 (q, J = 7.3Hz, 2H), 2.53(s, 3H), 2.08-2.02 (m, 2H), 1.96-1.90 (m, 2H), 1.17 (t, J = 7.7Hz, 3H)420 (M⁺ − 44), 185 (base) Example 9-356 Example 7-41 —

(DMSO-d₆) δ :10.20 (brs, 1H), 7.70 (d, J = 8.5Hz, 1H), 7.61 (s, 1H),7.46 (d, J = 8.1Hz, 1H), 7.44 (d, J = 1.9Hz, 1H), 7.35 (dd, J = 1.9,8.5Hz, 1H), 7.27 (d, J = 7.3Hz, 1H), 5.29 (s, 2 H), 4.10 (t, J = 6.2Hz,2H), 2.96 (t, J = 6.2Hz, 2H), 2.69 (q, J = 7.3Hz, 2H), 2.54 (s, 3H),2.09-2.00 (m, 2H), 1.98-1.89 (m, 2H), 1.18 (t, J = 7.3Hz, 3H) 480 (M⁺),278 (base) Example 9-357 Example 7-40 Example 3-6

(DMSO-d₆) δ :9.99 (brs, 1H), 8.20 (dd, J = 6.9, 8.9Hz, 1H), 7.69 (s,1H), 7.55 (d, J = 8.1Hz, 1H), 7.33 (d, J = 8.1Hz, 1 H), 7.13 (dd, J =2.7, 11.2Hz, 1H), 6.91 (dt, J = 2.7, 8.5Hz, 1H), 5.30 (s, 2H), 4.96 (s,2H), 4.22-4.15 (m, 4H), 4.00 (s, 3H), 2.67 (q, J = 7.3Hz, 2H), 1.17 (t,J = 7.3Hz, 3H) 482 (M⁺), 438, 278, 187 (base)

TABLE 101 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-358 Example 7-31 Example 3-6

(DMSO-d₆) δ :9.91 (brs, 1H), 8.07 (d, J = 8.1Hz, 1H), 7.68 (s, 1H), 7.55(d, J = 8.5Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.02 (s, 1H), 6.88 (d, J =7.3Hz, 1H), 5.29 (s, 2H), 4.96 (s, 2 H), 4.22-4.19 (m, 2H), 4.18- 4.15(m, 2H), 3.96 (s, 3H), 2.66 (q, J = 7.3Hz, 2H), 2.36 (s, 3H), 1.17 (t, J= 7.3Hz, 3H) 478 (M⁺), 434, 274, 187 (base) Example 9-359 Example 7-41Example 1-1

(DMSO-d₆) δ :10.21 (brs, 1H), 8.21 (s, 1H), 7.74 (s, 1H), 7.70 (d, J =8.5Hz, 1H), 7.59 (d, J = 8.1Hz, 1H), 7.44 (d, J = 1.9Hz, 1H), 7.39-7.32(m, 2H), 5.31 (s, 2H), 3.85 (s, 3H), 2.70 (q, J = 7.3Hz. 2H), 2.54 (s,3H), 1.18 (t, J = 7.3Hz, 3H) 440 (M⁺), 145 (base) Example 9-360 Example7-40 Example 4-3

(DMSO-d₆) δ :10.00 (brs, 1H), 8.20 (dd, J = 6.4, 8.9Hz, 1 H), 8.09 (s,1H), 7.84 (s, 1H), 7.71 (d, J = 8.5Hz, 1H), 7.47 (dd, J = 0.8, 8.5Hz,1H), 7.13 (dd, J = 2.3, 11.2Hz, 1H), 6.90 (dt, J = 2.7, 8.5Hz, 1H), 5.29(s, 2H), 4.45 (q, J = 7.3Hz, 2 H), 3.99 (s, 3H), 3.70-3.64 (m, 2H), 1.39(t, J = 7.3Hz, 3 H), 1.17 (t, J = 7.7Hz, 3H) 454 (M⁺), 410, 159 (base)Example 9-361 Example 7-30 Example 4-3

(DMSO-d₆) δ :10.15 (brs, 1H), 8.08 (s, 1H), 7.84 (s, 1H), 7.73-7.66 (m,2H), 7.46 (d, J = 8.5Hz, 1H), 7.21 (dd, J = 2.7, 10.0Hz, 1H), 7.12 (dt,J = 2.7, 8.5Hz, 1H), 5.29 (s, 2H), 4.45 (q, J = 7.3Hz, 2H), 2.68 (q, J =7.3Hz, 2H), 2.53 (s, 3 H), 1.39 (t, J = 7.3Hz, 3H), 1.17 (t, J = 7.3Hz,3H) 438 (M⁺), 159 (base)

TABLE 102 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-362 Example 7-41 Example 4-3

(DMSO-d₆) δ :10.21 (brs, 1H), 8.09 (s, 1H), 7.84 (s, 1H), 7.70 (d, J =8.5Hz, 2H), 7.47 (d, J = 8.9Hz, 1H), 7.44 (d, J = 1.9Hz, 1H), 7.35 (dd,J = 2.3, 8.5Hz, 1H), 5.30 (s, 2H), 4.45 (q, J = 7.3Hz, 2H), 2.69 (q, J =7.3Hz, 2H), 2.54 (s, 3H), 1.39 (t, 3H), 1.18 (t, J = 7.3Hz, 3H) 454(M⁺), 159 (base) Example 9-363 Example 7-30 Example 4-2

(DMSO-d₆) δ :10.17 (brs, 1H), 8.36 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J =6.2, 8.5Hz, 1H), 7.62 (d, J = 8.9Hz, 1H), 7.29 (d, J = 8.9Hz, 1H), 7.21(dd, J = 2.7, 10.0Hz, 1H), 7.12 (dt, J = 2.7, 8.5Hz, 1H), 5.24 (s, 2H),4.17 (s, 3H), 2.69 (q, J = 7.3Hz, 2H), 2.53 (s, 3H), 1.18 (t, J = 7.3Hz,3H) 424 (M⁺), 145 (base) Example 9-364 Example 7-28 Example 4-2

(DMSO-d₆) δ :10.07 (brs, 1H), 8.36 (s, 1H), 8.18 (d, J = 8.5 Hz, 1H),7.77 (s, 1H), 7.62 (d, J = 8.9Hz, 1H), 7.30-7.28 (m, 2H), 7.13 (dd, J =1.9, 8.5Hz, 1H), 5.24 (s, 2H), 4.17 (s, 3H), 4.01 (s, 3H), 2.70 (q, J =7.7Hz, 2H), 1.17 (t, J = 7.7 Hz, 3H) 456 (M⁺), 412 Example 9-365 Example7-31 Example 4-2

(DMSO-d₆) δ :9.92 (brs, 1H), 8.36 (s, 1H), 8.07 (d, J = 7.7Hz, 1H), 7.77(s, 1H), 7.62 (d, J = 8.9Hz, 1H), 7.29 (d, J = 8.9 Hz, 1H), 7.02 (s,1H), 6.88 (d, J = 8.1Hz, 1H), 5.23 (s, 2H), 4.17 (s, 3H), 3.96 (s, 3H),2.66 (q, J = 7.7Hz, 2H), 2.36 (s, 3H), 1.17 (t, J = 7.7Hz, 3H) 436 (M⁺),145 (base)

TABLE 103 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-366 Example 7-29 Example 4-2

(DMSO-d₆) δ :10.09 (brs, 1H), 8.36 (s, 1H), 7.77 (s, 1H), 7.61 (d, J =8.9Hz, 1H), 7.55 (d, J = 8.1Hz, 1H), 7.29 (d, J = 8.9Hz, 1H), 7.14 (s,1H), 7.10 (d, J = 7.7Hz, 1H), 5.23 (s, 2 H), 4.17 (s, 3H), 2.67 (q, J =7.3Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.18 (t, J = 7.3Hz, 3H) 420(M⁺), 145 (base) Example 9-367 Example 7-27 Example 4-4

(DMSO-d₆) δ :9.99 (brs, 1H), 8.41 (s, 1H), 8.19 (dd, J = 1.5, 7.7Hz,1H), 7.77 (s, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.39 (dt, J = 1.5, 7.3Hz,1H), 7.30 (d, J = 8.9Hz, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.06 (t, J =7.3Hz, 1H), 5.24 (s, 2H), 4.46 (q, J = 7.3Hz, 2H), 3.98 (s, 3H), 2.68(q, J = 6.9Hz, 2H), 1.51 (t, J = 6.9Hz, 3H), 1.18 (t, J = 7.3Hz, 3H) 436(M⁺), 159 (base) Example 9-368 Example 7-31 Example 4-4

(DMSO-d₆) δ :9.92 (brs, 1H), 8.41 (s, 1H), 8.07 (d, J = 8.1Hz, 1H), 7.77(s, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.02 (s,1H), 6.88 (d, J = 8.1Hz, 1H), 5.23 (s, 2H), 4.46 (q, J = 7.3Hz, 2H),3.96 (s, 3H), 2.66 (q, J = 7.3Hz, 2 H), 2.36 (s, 3H), 1.51 (t, J =7.3Hz, 3H), 1.17 (t, J = 7.3Hz, 3H) 450 (M⁺), 406, 274 Example 9-369Example 7-30 Example 4-4

(DMSO-d₆) δ :10.16 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.69 (dd, J =6.2, 8.9Hz, 1H), 7.63 (d, J = 8.9Hz, 1H), 7.29 (d, J = 8.9Hz, 1H), 7.21(dd, J = 2.7, 10.0Hz, 1H), 7.13 (dt, J = 2.7, 8.5Hz, 1H), 5.24 (s, 2H),4.46 (q, J = 7.3Hz, 2H), 2.69 (q, J = 7.3Hz, 2H), 2.53 (s, 3H), 1.51 (t,J = 7.3Hz, 3H), 1.18 (t, J = 7.3Hz, 3H) 438 (M⁺), 394

TABLE 104 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-370 Example 7-41 Example 4-4

(DMSO-d₆) δ :10.22 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.70 (d, J =8.5Hz, 1H), 7.63 (d, J = 9.2Hz, 1H), 7.44 (d, J = 1.9Hz, 1H), 7.35 (dd,J = 2.3, 8.5Hz, 1H), 7.30-7.28 (m, 1 H), 5.25 (s, 2H), 4.46 (q, J =7.3Hz, 2H), 2.70 (q, J = 7.3Hz, 2H), 2.54 (s, 3H), 1.51 (t, J = 7.3Hz,3H), 1.18 (t, J = 7.3Hz, 3H) 454 (M⁺), 410 Example 9-371 Example 7-29Example 4-4

(DMSO-d₆) δ : 10.09 (brs, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 7.63 (d, J =9.2Hz, 1H), 7.55 (d, J = 7.7Hz, 1H), 7.29 (d, J = 8.9Hz, 1H), 7.14 (s,1H), 7.10 (d, J = 8.1Hz, 1H), 5.24 (s, 2 H), 4.46 (q, J = 7.3Hz, 2H),2.67 (q, J = 7.3Hz, 2H), 2.50 (s, 3H), 2.31 (s, 3H), 1.51 (t, J = 7.3Hz,3H), 1.18 (t, J = 7.3Hz, 3H) 434 (M⁺), 390 Example 9-372 Example 7-311-Methyl- 1H- benzo- thiazole- 5- methanol

(DMSO-d₆) δ :9.97 (brs, 1H), 8.11 (s, 1H), 8.07 (d, J = 8.1Hz, 1H), 7.89(d, J = 8.5Hz, 1H), 7.64 (d, J = 8.5Hz, 1H), 7.02 (s, 1H), 6.88 (d, J =8.1Hz, 1H), 5.36 (s, 2H), 4.32 (s, 3H), 3.96 (s, 3H), 2.67 (q, J =7.7Hz, 2H), 2.36 (s, 3H), 1.18 (t, J = 7.7Hz, 3H) 437 (M⁺), 393 Example9-373 Example 7-28 Example 2-1

(DMSO-d₆) δ : 10.05 (brs, 1H), 8.18 (d, J = 8.5Hz, 1H), 7.61 (s, 1H),7.49 (d, J = 8.1Hz, 1H), 7.30 (s, 1H), 7.29 (d, J = 3.5, 1H), 7.13 (dd,J = 1.9, 8.5Hz, 1H), 5.28 (s, 2H), 4.01 (s, 3H), 3.73 (s, 3H), 2.69 (q,J = 7.5Hz, 2H), 2.53 (s, 3H), 1.17 (t, J = 7.5Hz, 3H) 470 (M⁺), 159(base)

TABLE 105 Carboxylic Hydroxy Mass, acid compound Example ¹H-NMR m/zExample 9-374 Example 7-31 Example 2-1

(DMSO-d₆) δ :9.90 (brs, 1H), 8.06 (d, J = 8.1Hz, 1H), 7.60 (s, 1H), 7.49(d, J = 8.1Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 7.02 (s, 1H), 6.88 (d, J =7.6Hz, 1H), 5.27 (s, 2H), 3.96 (s, 3 H), 3.73 (s, 3H), 2.66 (q, J =7.6Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.17 (t, J = 7.6Hz, 3H) 450(M⁺), 159 (base) Example 9-375 Example 7-29 Example 2-1

(DMSO-d₆) δ :10.07 (brs, 1H), 7.60 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H),7.48 (d, J = 8.1Hz, 1H), 7.27 (d, J = 7.7Hz, 1H), 7.14 (s, 1H), 7.10 (d,J = 8.1Hz, 1H), 5.28 (s, 2H), 3.73 (s, 3 H), 2.67 (q, J = 7.3Hz, 2H),2.53 (s, 3H), 2.31 (s, 3H), 1.17 (t, J = 7.3Hz, 3H) 434 (M⁺), 159 (base)Example 9-376 Example 7-41 Example 2-1

(DMSO-d₆) δ :10.20 (brs, 1H), 7.70 (d, J = 8.5Hz, 1H), 7.61 (s, 1H),7.49 (d, J = 8.1Hz, 1H), 7.44 (d, J = 1.9Hz, 1H), 7.35 (dd, J = 2.1,6.2Hz, 1H), 7.27 (d, J = 8.1Hz, 1H), 5.28 (s, 2 H), 3.73 (s, 3H), 3.28(s, 3H), 2.69 (q, J = 7.3Hz, 2H), 2.54 (s, 3H), 2.53 (s, 3H), 1.18 (t, J= 7.3Hz, 3H) 454 (M⁺), 278 (base) Example 9-377 Example 7-41 Example 3-6

(DMSO-d₆) δ :10.22 (brs, 1H), 7.70 (d, J = 8.5Hz, 1H), 7.55 (d, J =8.1Hz, 1H), 7.44 (s, 1H), 7.35 (dd, 2.3, 6.6Hz, 1H), 7.63 (d, J = 7.3Hz,1H), 5.31 (s, 2H), 4.96 (s, 2H), 4.21-4.16 (m, 4H), 2.70 (q, J = 7.3Hz,2H), 2.54 (s, 3H), 1.18 (t, J = 7.3Hz, 3H) 482 (M⁺), 278 (base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom or an alkoxy group); R′ represents an alkylgroup; and R″ represents an aryl or heterocyclic group which may have asubstituent (such as an alkyl group or an alkoxy group).

Example 10-1 Step 10-1-11-(4-Bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethanone

Under an ice cooling, N-methylpyrrole (8.10 g, 100 mmol) was dissolvedin methylene chloride (100 ml), and trichloroacetyl chloride (20.00 g,115 mmol) was added thereto. Thereafter, the mixture was stirred at aroom temperature for 16 hours. A saturated sodium hydrogen carbonateaqueous solution was added to the mixture. The organic phase wascollected by separation, washed with water, and dried over anhydrousmagnesium sulfate. The solvent was distilled off. Thus,2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (16.3 g, 72%) wasobtained. The resulting2,2,2-trichloro-1-(methyl-1H-pyrrol-2-yl)ethanone (15.0 g, 66.7 mmol)was dissolved in chloroform (150 ml), and N-bromosuccinimide (12.5 g,70.2 mmol) was added thereto at a room temperature. The mixture washeated under reflux for 16 hours. After the mixture was allowed to cool,a saturated sodium hydrogen carbonate aqueous solution was added to themixture. The organic phase was collected by separation, washed withwater, and dried over anhydrous magnesium sulfate. The solvent wasdistilled off. The resulting residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=1:9) to give the title compound(14.0 g, 69%).

¹H-NMR (DMSO-d₆) δ: 7.66 (d, J=1.5 Hz, 1H), 7.43 (d, J=1.5 Hz, 1H), 3.91(s, 3H)

Step 10-1-2 Ethyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate

In ethanol (100 ml),1-(4-bromo-1-methyl-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (12.1 g, 40mmol) prepared in the Step 10-1-1 was dissolved, and under an icecooling a 20% sodium ethoxide-ethanol solution was added thereto.Thereafter, the mixture was heated under reflux for 3 hours. After themixture was allowed to cool, the solvent was distilled off, and 3.5%hydrochloric acid (100 ml) and chloroform (150 ml) was added to themixture. The organic phase was collected by separation, washed with asaturated sodium hydrogen carbonate aqueous solution and water in order,and dried over anhydrous magnesium sulfate. The solvent was distilledoff, and the resulting residue was purified by silica gel columnchromatography (ethyl acetate:n-hexane=1:5) to give the title compound(7.39 g, 80%).

¹H-NMR (DMSO-d₆) δ: 7.28 (d, J=2.3 Hz, 1H), 6.85 (d, J=1.9 Hz, 1H), 4.21(q, J=7.3 Hz, 2H), 3.84 (s, 3H), 1.27 (t, J=7.3 Hz, 3H)

Mass, m/z: 231 (M⁺)

Step 10-1-3 Ethyl4-(4-chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate

Ethyl 4-bromo-1-methyl-1H-pyrrole-2-carboxylate (5.00 g, 21.6 mmol)prepared in the Step 10-1-2 was dissolved in N,N-dimethylformamide (20ml)/water (5 ml), and sodium carbonate (6.87 g, 64.8 mmol),tetrakis(triphenylphosphine)palladium (120 mg, 0.1 mmol) and4-chloro-2-methoxyphenylboronic acid (8.04 g, 4.32 mmol) was added tothe solution. The mixture was heated under reflux for 5 hours. After themixture was allowed to cool, water and chloroform was added to themixture. The organic phase was collected by separation and dried overanhydrous magnesium sulfate. The solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3) to give the title compound (3.23 g, 51%).

¹H-NMR (DMSO-d₆) δ: 7.59-7.56 (m, 2H), 7.25 (d, J=2.3 Hz, 1H), 7.11 (d,J=1.9 Hz, 1H), 6.98 (dd, J=1.9, 8.1 Hz, 1H), 4.24 (q, J=7.3 Hz, 2H),3.89 (s, 3H), 3.89 (s, 3H), 1.30 (t, J=7.3 Hz, 3H)

Mass, m/z: 293 (M⁺. base)

Step 10-1-4[4-(4-Chloro-2-methoxyphenyl)-1-methyl-1H-pyrrol-2-yl]carbamic acid4-methoxybenzyl ester

Ethyl 4-(4-chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylateprepared in the Step 10-1-3 was hydrolyzed according to the sameprocedure as in the Step 7-1-4 to give a carboxylic acid. The titlecompound was obtained according to the same procedure as in Example 9-1except that the resulting carboxylic acid and 4-methoxybenzyl alcoholwere used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol,respectively.

¹H-NMR (DMSO-d₆) δ: 9.00 (brs, 1H), 7.45 (d, J=8.1 Hz, 1H), 7.35 (d,J=6.6 Hz, 2H), 7.12 (d, J=1.9 Hz, 1H), 6.95-6.93 (m, 3H), 6.25 (s, 1H),5.05 (s, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.41 (s, 3H)

Mass, m/z: 400 (M⁺), 356, 235, 121 (base)

Example 10-2[4-(4-Chloro-2-methoxyphenyl)-1-methyl-1H-pyrrol-2-yl]carbamic acid1-methyl-1H-benzimidazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 10-1 except that the compound of Example 1-1 was used instead of4-methoxybenzyl alcohol.

¹H-NMR (DMSO-d₆) δ: 9.04 (brs, 1H), 8.20 (s, 1H), 7.75-7.65 (m, 1H),7.58 (d, J=8.1 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H), 7.33 (d, J=6.6 Hz, 1H),7.13 (d, J=1.9 Hz, 1H), 7.04 (d, J=1.9 Hz, 1H), 6.94 (dd, J=1.9, 8.5 Hz,1H), 6.26 (s, 1H), 5.23 (s, 3H), 3.86 (s, 3H), 3.84 (s, 3H), 3.42 (s,3H)

Mass, m/z: 424 (M⁺), 380, 262, 145 (base)

In the formulae, R and R′ are the same or different and each represent ahydrogen atom, an alkyl group or an alkoxyalkyl group, and R and R′ maybond together to form a 5- to 7-membered ring containing the nitrogenatom and the carbon atom adjacent to R and R′, respectively, asconstituent atoms thereof.

Example 11-1 Step 11-1 1-Methyl-1H-benzimidazole-5-carboxylic acid

Ethyl 1-methyl-1H-benzimidazole-5-carboxylate (800 mg, 3.92 mmol)prepared in the Step 1-1-4 was suspended in 2-propanol (10 ml), and a 1mol/L sodium hydroxide aqueous solution (10 ml) was added thereto. Themixture was heated under reflux for one hour. After being allowed tocool, the mixture was neutralized with 1 mol/L hydrochloric acid. Theresulting mixture was then acidified with citric acid, separated byfiltration, and washed with a small quantity of water. Then, theresulting product was subjected to through circulation drying overnightto give the title compound (595 mg, 86%) as a gray powder.

¹H-NMR (DMSO-d₆) δ: 12.74 (brs, 1H), 8.33 (s, 1H), 8.29 (s, 1H), 7.90(dd, J=1.5, 8.5 Hz, 1H), 7.65 (d, J=8.5 Hz, 1H), 3.88 (s, 3H)

Mass, m/z: 176 (M⁺, base), 159

Examples 11-2 to 11-15

The objective compounds were obtained according to the same procedure asin Example 11-1 except that any one of ester compounds obtained based onthe production process A shown in the following tables was used insteadof ethyl 1-methyl-1H-benzimidazole-5-carboxylate.

TABLE 106 Production process A Ester compound Example ¹H-NMR Mass, m/zStep 1-1-4 of Example 1-2 Ethyl 1-ethyl-1H- benzimidazole-5- carboxylate

(DMSO-d₆) δ: 12.60 (brs, 1H), 8.39 (s, 1H), 8.24 (s, 1H), 7.89 (d, J =8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H), 1.43(t, J = 7.3 Hz, 3H) 190 (M⁺), 175 (base) Step 1-1-4 of Example 1-3 Ethyl1-propyl-1H- benzimidazole-5- carboxylate

(DMSO-d₆) δ: 12.70 (brs, 1H), 8.41 (s, 1H), 8.24 (d, J = 1.2 Hz, 1H),7.88 (dd, J = 1.5, 8.5 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 4.26 (t, J =7.3 Hz, 2H), 1.88-1.79 (m, 2H), 0.85 (t, J = 7.3 Hz, 3H) 204 (M⁺), 175(base) Step 2-1-1 of Example 2-3 Ethyl 1-ethyl-2- methyl-1H-benzimidazole-5- carboxylate

(DMSO-d₆) δ: 12.61 (brs, 1H), 8.11 (s, 1H), 7.82 (dd, J = 1.5, 8.5 Hz,1H), 7.58 (d, J = 8.5 Hz, 1H), 4.25 (t, J = 7.3 Hz, 2H), 2.57 (s, 3H),1.31 (t, J = 7.3 Hz, 3H) 204 (M⁺, base), 189 Step 3-1-3 of Example 3-6Ethyl 3,4-dihydro- 1H-2-oxa-4a,9- diazafluorene-7- carboxylate

(DMSO-d₆) δ: 12.74 (brs, 1H), 8.17 (d, J = 1.5 Hz, 1H), 7.87 (dd, J =1.5, 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 4.99 (s, 2H), 4.26-4.24 (m,2H), 4.19-4.16 (m, 2H) 218 (M⁺, base) Step 3-1-3 of Example 3-2 Ethyl2,3-dihydro- 1H-2- benzo[d]pyrrolo[1,2- a]imidazole-6- carboxylate

(DMSO-d₆) δ: 8.16 (d, J = 1.5 Hz, 1H), 7.88 (dd, J = 1.5, 8.5 Hz, 1H),7.60 (d, J = 8.5 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.08 (t, J = 7.3 Hz,2H), 2.72-2.64 (m, 2H) 202 (M⁺, base) Step 3-1-3 of Example 3-1 Ethyl1,2,3,4- tetrahydrobenzo[4,5] imidazo[1,2- a]pyridine-7- carboxylate

(DMSO-d₆) δ: 12.62 (brs, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.82 (dd, J =1.5, 8.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 4.15-4.12 (m, 2H), 3.01-2.98(m, 2H), 2.09-2.03 (m, 2H), 1.98-1.92 (m, 2H) 216 (M⁺, base) Step 3-1-3of Example 3-3 Ethyl 7,8,9,10- tetrahydro-6H- benzo[4,5]imidazo[1,2-a]azepine-3- carboxylate

(DMSO-d₆) δ: 12.63 (brs, 1H), 8.11 (d, J = 1.5 Hz, 1H), 7.83 (dd, J =1.5, 8.5 Hz, 1H), 7.61 (d, J = 8.9 Hz, 1H), 4.30 (t, J = 5.0 Hz, 2H),3.08-3.05 (m, 2H), 1.91-1.86 (m, 2H), 1.77-1.74 (m, 2H), 1.72-1.68 (m,2H) 230 (M⁺, base)

TABLE 107 Production process A Ester compound Example ¹H-NMR Mass, m/zStep 3-1-3 of Example 3-4 Ethyl 1-methyl- 1,2,3,4- tetrahydrobenzo[4,5]imidazo[1,2- a]pyridine-7- carboxylate

(DMSO-d₆) δ: 12.60 (brs, 1H), 8.11 (d, J = 1.2 Hz, 1H), 7.82 (dd, J =1.5, 8.5 Hz, 1H), 7.60 (d, J = 8.5 Hz, 1H), 4.74-4.70 (m, 1H), 3.06-3.00(m, 1H), 2.97-2.88 (m, 1H), 2.19-2.11 (m, 1H), 2.07-1.99 (m, 1H),1.95-1.85 (m, 2H), 1.45 (d, J = 6.6 Hz, 3H) 230 (M⁺), 215 (base) Step4-1-3 of Example 4-1 Ethyl 1-methyl-1H- indazole-5- carboxylate

(DMSO-d₆) δ: 12.75 (brs, 1H), 8.44 (dd, J = 0.8, 1.5 Hz, 1H), 8.22 (d, J= 0.8 Hz, 1H), 7.95 (dd, J = 1.5, 8.9 Hz, 1H), 7.70 (d, J = 8.9 Hz, 1H),4.08 (s, 3H) 176 (M⁺, base) Step 4-1-3 of Example 4-3 Ethyl 1-ethyl-1H-indazole-5- carboxylate

(DMSO-d₆) δ: 12.68 (brs, 1H), 8.44 (dd, J = 0.8, 1.5 Hz, 1H), 8.23 (d, J= 1.2 Hz, 1H), 7.94 (dd, J = 1.5, 8.9 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H),4.46 (q, J = 7.3 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H) 190 (M⁺, base), 175Step 4-1-3 of Example 4-2 Ethyl 2-methyl-2H- indazole-5- carboxylate

(DMSO-d₆) δ: 12.64 (brs, 1H), 8.55 (s, 1H), 8.45 (d, J = 0.8 Hz, 1H),7.74 (dd, J = 1.5, 8.9 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 4.20 (s, 3H)176 (M⁺, base) Step 4-1-3 of Example 4-4 Ethyl 2-ethyl-2H- indazole-5-carboxylate

(DMSO-d₆) δ: 12.60 (brs, 1H), 8.59 (s, 1H), 8.45 (dd, J = 0.8, 1.5 Hz,1H) 7.75 (dd, J = 1.5, 9.3 Hz, 1H), 7.64 (d, J = 8.9 Hz, 1H), 4.49 (q, J= 7.3 Hz, 2H), 1.52 (t, J = 7.3 Hz, 3H) 190 (M⁺), 162 (base) Step 1-1-4of Example 1-6 Ethyl 1-(2- methoxyethyl)-1H- benzimidazole-5-carboxylate

(DMSO-d₆) δ: 12.68 (brs, 1H), 8.31 (s, 1H), 8.23 (d, J = 0.8 Hz, 1H),7.88 (dd, J = 1.5, 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 4.46 (t, J =5.4 Hz, 2H), 3.79 (t, J = 5.4 Hz, 2H), 3.23 (s, 3H) 220 (M⁺), 175 (base)Step 2-1-1 of Example 2-4 Ethyl 2- methoxyethyl-1- methyl-1H-benzimidazole-5- carboxylate

(DMSO-d₆) δ: 8.21 (d, J = 1.5 Hz, 1H), 7.90 (dd, J = 1.5, 8.5 Hz, 1H),7.65 (d, J = 8.5 Hz, 1H), 4.73 (s, 2H), 3.85 (s, 3H), 3.34 (s, 3H) 220(M⁺), 190 (base)

In the formulae, R represents a carbocyclic (homocyclic) or heterocyclicgroup which may have a substituent (such as a halogen atom, an alkylgroup, or an alkoxy group), and R′ represents a hydrogen atom or analkyl group.

Example 12-1 Step 12-1[2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]methanol

Lithium aluminum hydride (380 mg, 10.0 mmol) was suspended intetrahydrofuran (10 ml), and a suspension (10 ml) of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (1.42 g,5.00 mmol) prepared in Example 7-1 in tetrahydrofuran was added theretoat a room temperature. The mixture was stirred for 3 hours at a roomtemperature. Under an ice cooling, 5 drops of a saturated sodiumbicarbonate solution were slowly added to the mixture. Ethyl acetate wasadded to the mixture, and another 5 drops of a saturated sodiumbicarbonate solution were added thereto. The precipitate was removed byfiltration, and the removed solid was washed with chloroform. Thewashings and the filtrate were concentrated together. The concentratewas purified by silica gel column chromatography(chloroform:methanol=20:1) to give the title compound (580 mg, 43%) as alight-brown powder.

¹H-NMR (DMSO-d₆) δ: 8.21 (d, J=8.5 Hz, 1H), 7.32 (d, J=1.2 Hz, 1H), 7.14(dd, J=1.5, 8.5 Hz, 1H), 5.44 (t, J=5.4 Hz, 1H), 4.65 (d, J=5.4 Hz, 1H),4.03 (s, 3H), 2.35 (s, 3H)

Mass, m/z: 269 (M⁺, base), 130

Examples 12-2 to 12-17, 12-19 to 12-25, 12-30, and 12-32 to 12-34

The objective compounds were obtained according to the same procedure asin Example 12-1 except that any one of carboxylic acids of Examplesshown in the following tables was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

TABLE 108 Carboxylic acid Example ¹H-NMR Mass, m/z Example 7-9 

(DMSO-d₆) δ: 7.69 (d, J = 7.3 Hz, 1H), 7.38-7.34 (m, 2H), 7.32-7.28 (m,1H), 5.51 (t, J = 5.8 Hz, 1H), 4.66 (d, J = 5.8 Hz, 2H), 2.53 (s, 3H),2.36 (s, 3H) 219 (M⁺, base) Example 7-8 

(DMSO-d₆) δ: 8.22 (dd, J = 1.5, 7.7 Hz, 1H), 7.45-7.40 (m, 1H), 7.20 (d,J = 8.5 Hz, 1H), 7.09-7.05 (m, 1H), 5.40 (t, J = 5.4 Hz, 1H), 4.65 (d, J= 5.4 Hz, 2H), 3.99 (s, 3H), 2.35 (s, 3H) 235 (M⁺), 130 (base) Example7-14

(DMSO-d₆) δ: 8.09 (d, J = 7.7 Hz, 1H), 7.04 (s, 1H), 6.89 (dd, J = 0.8,7.7 Hz, 1H), 5.37 (t, J = 5.4 Hz, 1H), 4.63 (d, J = 5.4 Hz, 2H), 3.97(s, 3H), 2.36 (s, 3H), 2.34 (s, 3H) 249 (M⁺, base) Example 7-15

(DMSO-d₆) δ: 8.13 (d, J = 8.5 Hz, 1H), 6.74 (d, J = 2.3 Hz, 1H), 6.67(dd, J = 2.3, 8.5 Hz, 1H), 5.33 (t, J = 5.4 Hz, 1H), 4.62 (d, J = 5.4Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H), 2.33 (s, 3H) 265 (M⁺, base) Example7-16

(DMSO-d₆) δ: 7.59 (d, J = 8.1 Hz, 1H), 7.16 (s, 1H), 7.11 (d, J = 8.1Hz, 1H), 5.48 (t, J = 5.4 Hz, 1H), 4.64 (d, J = 5.4 Hz, 1H), 2.50 (s,3H), 2.35 (s, 3H), 2.31 (s, 3H) 233 (M⁺, base) Example 7-6 

(DMSO-d₆) δ: 7.72 (dd, J = 6.2, 8.9 Hz, 1H), 7.22 (dd, J = 2.7, 10.0 Hz,1H), 7.13 (dt, J = 2.7, 8.5 Hz, 1H), 5.52 (t, J = 5.8 Hz, 1H), 4.66 (d,J = 5.8 Hz, 1H), 2.53 (s, 3H), 2.36 (s, 3H) 237 (M⁺, base) Example 7-7 

(DMSO-d₆) δ: 7.73 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 2.3 Hz, 1H), 7.37(dd, J = 2.3, 8.5 Hz, 1H), 5.54 (t, J = 5.4 Hz, 1H), 4.66 (d, J = 5.4Hz, 1H), 2.54 (s, 3H), 2.36 (s, 3H) 253 (M⁺, base)

TABLE 109 Carboxylic acid Example ¹H-NMR Mass, m/z Example 7-5 

(DMSO-d₆) δ: 8.18 (dd, J = 6.2, 8.9 Hz, 1H), 7.63 (dd, J = 2.3, 8.5 Hz,1H), 7.37 (ddd, J = 2.7, 8.1, 8.9 Hz, 1H), 5.57 (t, J = 5.4 Hz, 1H),4.67 (d, J = 5.4 Hz, 1H), 2.37 (s, 3H) 257 (M⁺), 71 (base) Example 7-21

(DMSO-d₆) δ: 7.83 (dd, J = 0.8, 1.9 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H),6.66 (dd, J = 1.9, 3.6 Hz, 1H), 5.53 (t, J = 5.8 Hz, 1H), 4.63 (d, J =5.8 Hz, 2H), 2.31 (s, 3H) 195 (M⁺, base) Example 7-23

(DMSO-d₆) δ: 7.65 (dd, J = 1.2, 5.4 Hz, 1H), 7.55 (dd, J = 0.8, 5.4 Hz,1H), 7.14 (dd, J = 3.9, 5.0 Hz, 1H), 5.51 (t, J = 5.4 Hz, 1H), 4.63 (d,J = 5.4 Hz, 2H), 2.29 (s, 3H) 211 (M⁺, base) Example 7-24

(DMSO-d₆) δ: 7.76 (d, J = 5.4 Hz, 1H), 7.21 (d, J = 5.4 Hz, 1H), 5.58(t, J = 5.8 Hz, 1H), 4.67 (d, J = 5.8 Hz, 2H), 2.33 (s, 3H) 245 (M⁺,base) Example 7-39

(DMSO-d₆) δ: 8.45 (dd, J = 1.2, 4.6 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H),7.33 (dd, J = 4.6, 7.7 Hz, 1H), 5.48 (t, J = 5.8 Hz, 1H), 4.65 (d, J =5.8 Hz, 2H), 2.72 (s, 3H), 2.37 (s, 3H) 211 (M⁺, base) Example 7-33

(CDCl₃) δ: 8.34 (dd, J = 1.9, 8.1 Hz, 1H), 7.75 (s, 1H), 7.39 (dt, J =1.5, 7.3 Hz, 1H), 7.07 (dt, J = 0.8, 7.3 Hz, 1H), 7.03 (d, J = 8.1 Hz,1H), 4.92 (s, 2H), 4.02 (s, 3H) 211 (M⁺), 116 (base) Example 7-28

(CDCl₃) δ: 8.30 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H),6.99 (d, J = 1.9 Hz, 1H), 4.85 (d, J = 5.4 Hz, 2H), 4.00 (s, 3H),3.72-3.68 (m, 1H), 2.79 (q, J = 7.3 Hz, 2H), 1.31 (t, J = 7.3 Hz, 3H)283 (M⁺), 144 (base)

TABLE 110 Carboxylic acid Example ¹H-NMR Mass, m/z Example 7-34

(CDCl₃) δ: 8.30 (d, J = 8.5 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H),6.99 (d, J = 1.9 Hz, 1H), 4.84 (d, J = 5.8 Hz, 2H), 4.00 (s, 3H), 3.69(t, J = 5.8 Hz, 1H), 2.74 (t, J = 7.3 Hz, 2H), 1.76 (sextet, J = 7.3 Hz,2H), 0.96 (t, J = 7.3 Hz, 3H) 297 (M⁺, base) Example 8-34

(DMSO-d₆) δ: 7.72 (dd, J = 2.3, 7.7 Hz, 1H), 6.89 (s, 1H), 6.65 (d, J =7.7 Hz, 1H), 6.59 (s, 1H), 5.22 (t, J = 5.4 Hz, 1H), 4.51 (d, J = 5.8Hz, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 2.32 (s, 3H) 232 (M⁺) Example 8-33

(DMSO-d₆) δ: 7.83 (dd, J = 6.9, 8.5 Hz, 1H), 6.97 (dd, J = 2.7, 11.6 Hz,1H), 6.81-6.76 (m, 1H), 6.59 (s, 1H), 5.24 (t, J = 5.8 Hz, 1H), 4.51 (d,J = 5.8 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 3H) 236 (M⁺, base) Example 8-9 

(DMSO-d₆) δ: 7.85 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 7.02(dd, J =1.9, 8.1 Hz, 1H), 6.63 (s, 1H), 5.25 (t, J = 5.8 Hz, 1H), 4.52(d, J = 5.8 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H) 252 (M⁺), 56 (base)Example 8-7 

(DMSO-d₆) δ: 7.84 (dd, J = 1.5, 7.7 Hz, 1H), 7.26 (ddd, J = 1.5, 7.3,8.9 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (dt, 0.8, 7.3 Hz, 1H), 6.63(s, 1H), 5.24 (t, J = 5.4 Hz, 1H), 4.52 (d, J = 5.4 Hz, 2H), 3.84 (s,3H), 3.83 (s, 3H) 218 (M⁺, base) Example 8-32

(DMSO-d₆) δ: 7.85 (dd, J = 1.5, 7.7 Hz, 1H), 7.26 (ddd, J = 1.5, 7.3,8.5 Hz, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.96 (dt, 0.8, 7.7 Hz, 1H), 6.62(s, 1H), 5.26 (t, J = 5.4 Hz, 1H), 4.53 (d, J = 5.4 Hz, 2H), 4.16 (q, J= 7.3 Hz, 2H), 3.85 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H) 232 (M⁺, base)

TABLE 111 Carboxylic acid Example ¹H-NMR Mass, m/z Example 8-12

(DMSO-d₆) δ: 7.73 (d, J = 7.7 Hz, 1H), 6.89 (s, 1H), 6.77 (d, J = 7.7Hz, 1H), 6.57 (s, 1H), 5.24 (t, J = 5.8 Hz, 1H), 4.51 (d, J = 5.8 Hz,2H), 4.14 (q, J = 7.3 Hz, 2H), 3.83 (s, 3H), 2.32 (s, 3H), 1.36 (t, J =7.3 Hz, 3H) 246 (M⁺, base) Example 8-8 

(DMSO-d₆) δ: 7.85 (dd, J = 6.9, 8.5 Hz, 1H), 6.97 (dd, J = 2.3, 11.2 Hz,1H), 6.79 (dt, J = 2.3, 8.5 Hz, 1H), 6.57 (s, 1H), 5.26 (t, J = 5.4 Hz,1H), 4.52 (d, J = 5.4 Hz, 2H), 4.15 (q, J = 7.3 Hz, 2H), 3.86 (s, 3H),1.36 (t, J = 7.3 Hz, 3H) 250 (M⁺, base) Example 8-17

(DMSO-d₆) δ: 7.41 (d, J = 8.1 Hz, 1H), 7.05 (s, 1H), 7.01 (d, J = 7.7Hz, 1H), 6.35 (s, 1H), 5.28 (t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.4 Hz,2H), 4.15 (q, J = 7.3 Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H), 1.38 (t, J =7.3 Hz, 3H) 230 (M⁺, base) Example 8-27

(DMSO-d₆) δ: 7.27-7.24 (m, 2H), 7.12-7.10 (m, 1H), 6.18 (s, 1H), 4.97(t, J = 5.4 Hz, 1H), 4.39 (d, J = 5.8 Hz, 2H), 3.83 (s, 3H), 3.55 (s,3H) 252 (M⁺, base) Example 8-26

(DMSO-d₆) δ: 7.27 (dd, J = 6.9, 8.1 Hz, 1H), 7.09-7.04 (m, 1H), 6.87(dt, J = 2.3, 8.5 Hz, 1H), 4.95 (t, J = 5.8 Hz, 1H), 4.39 (d, J = 5.8Hz, 2H), 3.81 (s, 3H), 3.54 (s, 3H) 236 (M⁺) Example 8-10

(DMSO-d₆) δ: 7.85 (dd, J = 1.5, 7.7 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H),6.96 (dt, J = 0.8, 7.3 Hz, 1H), 6.61 (s, 1H), 5.25 (t, J = 5.4 Hz, 1H),4.53 (d, J = 5.4 Hz, 2H), 4.15 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 1.37(t, J = 7.3 Hz, 3H) 266 (M⁺)

TABLE 112 Carbox- ylic Mass, acid Example ¹H-NMR m/z Exam- ple 7-30

(DMSO-d₆) δ: 7.73 (dd, J = 6.2, 8.9 Hz, 1H), 7.22 (dd, J = 2.7, 10.1 Hz,1H), 7.13 (dt, J = 2.7, 8.5 Hz, 1H), 5.52 (t, J = 5.4 Hz, 1H), 4.67 (d,J = 5.4 Hz, 2H), 2.70 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 1.23 (t, J =7.3 Hz, 1H) 251 (M⁺, base)

Example 12-18[5-(2-Methoxy-4-methylphenyl)-1-methyl-1H-pyrazol-3-yl]methanol

Ethyl 5-(2-methoxy-4-methylphenyl)-1-methyl-1H-pyrazole-3-carboxylateobtained in the Step 8-1-2 of Example 8-34 was subjected to the sameprocedure as in the Step 8-1-3 to give a carboxylic acid. The titlecompound was obtained according to the same procedure as in Example 12-1except that the resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.11 (d, J=7.7 Hz, 1H), 6.98 (s, 1H), 6.85 (d, J=7.3Hz, 1H), 6.12 (s, 1H), 4.94 (t, J=5.8 Hz, 1H), 4.39 (d, J=5.8 Hz, 2H),3.78 (s, 3H), 3.54 (s, 3H), 2.37 (s, 3H)

Mass, m/z: 232 (M⁺, base)

Example 12-261-Ethyl-[5-(4-fluoro-2-methoxyphenyl)-1H-pyrazol-3-yl]methanol

Ethyl 1-ethyl-5-(4-fluoro-2-methoxyphenyl)-1H-pyrazole-3-carboxylateobtained in the Step 8-1-2 of Example 8-8 was subjected to the sameprocedure as in the Step 8-1-3 to give a carboxylic acid. The titlecompound was obtained in the same procedure as in Example 12-1 exceptthat the resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.25 (dd, J=6.9, 8.5 Hz, 1H), 7.07 (dd, J=2.3, 11.2Hz, 1H), 6.87 (dt, J=2.3, 8.5 Hz, 1H), 6.11 (s, 1H), 5.00 (brs, 1H),4.41 (d, J=4.2 Hz, 2H), 3.79 (s, 3H), 3.78 (q, J=7.3 Hz, 2H), 1.22 (t,J=7.3 Hz, 3H)

Mass, m/z: 250 (M⁺, base)

Example 12-27 1-Ethyl-[5-(2-methoxyphenyl)-1H-pyrazol-3-yl]methanol

Ethyl 1-ethyl-5-(2-methoxyphenyl)-1H-pyrazole-3-carboxylate obtained inthe Step 8-1-2 of Example 8-32 was subjected to the same procedure as inthe Step 8-1-3 to give a carboxylic acid. The title compound wasobtained according to the same procedure as in Example 12-1 except thatthe resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.45 (dt, J=1.9, 7.7 Hz, 1H), 7.22 (dd, J=1.9, 7.7Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.06-7.02 (m, 1H), 6.12 (s, 1H), 4.97(t, J=5.8 Hz, 1H), 4.42 (d, J=5.4 Hz, 2H), 3.80 (q, J=7.3 Hz, 2H), 3.78(s, 3H), 1.22 (t, J=7.3 Hz, 3H)

Mass, m/z: 232 (M⁺, base)

Example 12-28[5-(4-Chloro-2-methoxyphenyl)-1-ethyl-1H-pyrazol-3-yl]methanol

Ethyl 5-(4-chloro-2-methoxyphenyl)-1-ethyl-1H-pyrazole-3-carboxylateobtained in the Step 8-1-2 of Example 8-10 was subjected to the sameprocedure as in the Step 8-1-3 to give a carboxylic acid. The titlecompound was obtained according to the same procedure as in Example 12-1except that the resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.25-7.23 (m, 2H), 7.11 (dd, J=1.9, 8.1 Hz, 1H),6.13 (s, 1H), 4.98 (t, J=5.8 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 3.82-3.77(m, 5H), 1.22 (t, J=7.3 Hz, 3H)

Mass, m/z: 266 (M⁺, base)

Example 12-291-Ethyl-[5-(2-methoxy-4-methylphenyl)-1H-pyrazol-3-yl]methanol

Ethyl 1-ethyl-5-(2-methoxy-4-methylphenyl)-1H-pyrazole-3-carboxylateobtained in the Step 8-1-2 of Example 8-12 was subjected to the sameprocedure as in the Step 8-1-3 to give a carboxylic acid. The titlecompound was obtained according to the same procedure as in Example 12-1except that the resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.08 (d, J=7.7 Hz, 1H), 6.97 (s, 1H), 6.85 (dd,J=0.8, 7.3 Hz, 1H), 6.08 (s, 1H), 4.95 (t, J=5.8 Hz, 1H), 4.40 (d, J=5.8Hz, 2H), 3.82-3.76 (m, 2H), 3.76 (s, 3H), 2.37 (s, 3H), 1.21 (t, J=7.3Hz, 3H)

Mass, m/z: 246 (M⁺, base)

Example 12-31 [5-(2,4-Dimethylphenyl)-1-methyl-1H-pyrazol-3-yl]methanol

Ethyl 5-(2,4-dimethylphenyl)-1-methyl-1H-pyrazole-3-carboxylate obtainedin the Step 8-1-2 of Example 8-16 was subjected to the same procedure asin the Step 8-1-3 to give a carboxylic acid. The title compound wasobtained according to the same procedure as in Example 12-1 except thatthe resulting carboxylic acid was used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

¹H-NMR (DMSO-d₆) δ: 7.17 (s, 1H), 7.11 (s, 2H), 6.14 (s, 1H), 4.97 (t,J=5.8 Hz, 1H), 4.41 (d, J=5.8 Hz, 2H), 3.51 (s, 3H), 2.33 (s, 3H), 2.10(s, 3H)

Mass, m/z: 216 (M⁺, base)

In the formulae, Ar represents a thiazole or pyrazole ring which mayhave a carbocyclic (homocyclic) or heterocyclic group as a substituent;R and R′ are the same or different and each represent a hydrogen atom, ahalogen atom, an alkyl group or an alkoxy group; and R″ represents acarbocyclic (homocyclic) or heterocyclic group which may have asubstituent (such as a halogen atom, an alkyl group, an alkoxy group, oran alkoxyalkyl group).

Example 13-1 Step 13-1 (1-Methyl-1H-benzimidazol-5-yl)carbamic acid4-methyl-2-(2-methylphenyl)thiazol-5-ylmethyl ester

In toluene (3 ml), [2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol (80mg, 0.37 mmol) prepared in Example 12-2 and1-methyl-1H-benzimidazole-5-carboxylic acid (77 mg, 0.44 mmol) preparedin Example 11-1 were suspended, and triethylamine (48 mg, 0.47=1) andthen diphenylphosphoryl azide (0.12 g, 0.44 mmol) were added thereto.The mixture was heated under reflux for one hour. After being allowed tocool, the mixture was purified by silica gel column chromatography(ethyl acetate:methanol=20:1) to give the title compound (0.11 g, 75%)as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 9.71 (brs, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.72 (d,J=7.3 Hz, 1H), 7.46 (d, J=8.5 Hz, 1H), 7.40-7.35 (m, 2H), 7.33-7.29 (m,2H), 5.34 (s, 2H), 3.80 (s, 3H), 2.54 (s, 3H), 2.50 (s, 3H)

Mass, m/z: 348 (M⁺-44), 173 (base)

Examples 13-2 to 13-150

The objective compounds were obtained according to the same procedure asin Example 13-1 except that hydroxy compounds or carboxylic acids knownor obtained in Examples as shown in the following tables were usedinstead of [2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol or1-methyl-1H-benzimidazole-5-carboxylic acid.

TABLE 113 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-6 4-Methoxy benzoic acid

(DMSO-d₆) δ: 9.57 (brs, 1H), 7.61 (d, J = 8.1 Hz, 1H), 7.37-7.32 (m,2H), 7.17 (s, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.89-6.84 (m, 2H), 5.34 (s,2H), 3.71 (s, 3H), 2.50 (s, 3H), 2.47 (s, 3H), 2.32 (s, 3H) 338 (M⁺ −44), 216 (base) Example 12-8 1-Methyl-1H- benzotriazole- 5-carboxylicacid

(DMSO-d₆) δ: 10.03 (brs, 1H), 8.16 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H),7.55 (dd, J = 1.9, 9.2 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.38 (dd, J =1.9, 8.1 Hz, 1H), 5.43 (s, 2H), 4.26 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H)427 (M⁺), 383, 236 (base) Example 12-3 —

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.25 (dd, J = 1.9, 8.1 Hz, 1H), 8.11 (s,1H), 7.81 (s, 1H), 7.48-7.44 (m, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.24 (d,J = 8.5 Hz, 1H), 7.11-7.07 (m, 1H), 5.37 (s, 2H), 4.00 (s, 3H), 3.80 (s,3H), 2.49 (s, 3H) 364 (M⁺ − 44), 218 (base) Example 12-1 —

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.11 (s, 1H),7.80 (s, 1H), 7.46 (d, J = 8.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.32(dd, J = 0.8, 8.5 Hz, 1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.37 (s, 2H),4.04 (s, 3H), 3.80 (s, 3H), 2.49 (s, 3H) 398 (M⁺ − 44), 173 (base)Example 12-4 —

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.13 (d, J = 8.1 Hz, 1H), 8.10 (s, 1H),7.80 (s, 1H), 7.45 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.06(s, 1H), 6.91 (d, J = 7.3 Hz, 1H), 5.35 (s, 2H), 3.99 (s, 3H), 3.80 (s,3H), 2.47 (s, 3H), 2.37 (s, 3H) 378 (M⁺ − 44), 232 (base)

TABLE 114 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-5 —

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.17 (d, J = 8.9 Hz, 1H), 8.11 (s, 1H),7.80 (s, H), 7.45 (d, J = 8.9 Hz, 1H), 7.32 (dd, J = 1.2, 8.5 Hz, 1H),6.76 (d, J = 2.3 Hz, 1H), 6.68 (dd, J = 2.3, 8.5 Hz, 1H), 5.37 (s, 2H),4.03 (s, 3H), 4.00 (s, 3H), 3.84 (s, 3H), 2.46 (s, 3H) 394 (M⁺ − 44),248 (base) Example 12-6 —

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.13 (s, 1H), 7.81 (s, 1H), 7.62 (d, J =8.1 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 7.33 (dd, J = 1.2, 8.1 Hz, 1H),7.17 (s, 1H), 7.12 (dd, J = 1.2, 7.7 Hz, 1H), 5.37 (s, 2H), 3.80 (s,3H), 2.50 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H) 362 (M⁺ − 44), 216 (base)Example 12-7 —

(DMSO-d₆) δ: 9.72 (brs, 1H), 8.15 (s, 1H), 7.82 (s, 1H), 7.76 (dd, J =6.2, 8.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.33 (dd, J = 0.8, 8.9 Hz,1H), 7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.15 (dt, J = 2.7, 8.5 Hz, 1H),5.39 (s, 2H), 3.81 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H) 410 (M⁺), 366,220 (base) Example 12-8 —

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.11 (s, 1H), 7.80 (s, 1H), 7.76 (d, J =8.5 Hz, 1H), 7.50-7.45 (m, 2H), 7.38 (dd, J = 1.9, 8.1 Hz, 1H), 7.32 (d,J = 8.5 Hz, 1H), 5.39 (s, 2H), 3.80 (s, 3H), 2.54 (s, 3H), 2.50 (s, 3H)382 (M⁺ − 44), 173 (base) Example 12-9 —

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.23 (dd, J = 6.2, 8.9 Hz, 1H), 8.11 (s,1H), 7.80 (s, 1H), 7.66 (dd, J = 2.7, 8.9 Hz, 1H), 7.46 (d, J = 8.9 Hz,1H), 7.39 (dt, J = 2.7, 8.1 Hz, 1H), 7.34-7.30 (m, 1H), 5.40 (s, 2H),3.80 (s, 3H), 2.50 (s, 3H) 430 (M⁺), 386, 240 (base)

TABLE 115 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/z —Example 11-2

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.18 (s, 1H), 7.81 (s, 1H), 7.72 (d, J =7.3 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.38-7.36 (m, 2H), 7.35-7.29 (m,2H), 5.39 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 2.49 (s, 3H),1.40 (t, J = 7.3 Hz, 3H) 406 (M⁺), 362, 202 (base) Example 12-1 Example11-2

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.25 (d, J = 8.9 Hz, 1H), 8.18 (s, 1H),7.80 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.31(d, J = 8.5 Hz, 1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.37 (s, 2H), 4.23(q, J = 7.3 Hz, 2H), 4.04 (s, 3H), 2.49 (s, 3H), 1.40 (t, J = 7.3 Hz,3H) 456 (M⁺), 412, 252 (base) Example 12-4 Example 11-2

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.17 (s, 1H), 8.13 (d, J = 8.1 Hz, 1H),7.80 (s, 1H), 7.49 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.06(s, 1H), 6.91 (dd, J = 0.8, 8.1 Hz, 1H), 5.35 (s, 2H), 4.23 (q, J = 7.3Hz, 2H), 3.99 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H), 1.40 (t, J = 7.3 Hz,3H) 392 (M⁺ − 44), 187 (base) Example 12-6 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.62 (d, J =7.7 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 7.17(s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.37 (s, 2H), 4.23 (q, J = 7.3 Hz,2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H)420 (M⁺), 376, 233 (base) Example 12-7 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.77 (dd, J =6.2, 8.9 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H),7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.14 (dt, J = 2.7, 8.5 Hz, 1H), 5.38(s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 2.49 (s, 3H), 1.40 (t,J = 7.3 Hz, 3H) 424 (M⁺), 380, 220 (base)

TABLE 116 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-8 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.76 (d, J =8.5 Hz, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.48 (s, 1H), 7.38 (dd, J = 2.3,8.5 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 5.39 (s, 2H), 4.23 (q, J = 7.3Hz, 2H), 2.55 (s, 3H), 2.50 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H) 396 (M⁺ −44), 187 (base) Example 12-9 Example 11-2

(DMSO-d₆) δ: 9.72 (brs, 1H), 8.23 (dd, J = 6.2, 8.9 Hz, 1H), 8.20 (s,1H), 7.81 (s, 1H), 7.66 (dd, J = 2.7, 8.9 Hz, 1H), 7.51 (d, J = 8.9 Hz,1H), 7.39 (ddd, J = 2.7, 8.1, 8.9 Hz, 1H), 7.31 (dd, J = 1.9, 8.5 Hz,1H), 5.40 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 2.49 (s, 3H), 1.40 (t, J =7.3 Hz, 3H) 444 (M⁺), 400, 240 (base) Example 12-6 Example 11-3

(DMSO-d₆) δ: 9.69 (brs, 1H), 8.15 (s, 1H), 7.80 (s, 1H), 7.62 (d, J =7.7 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 9.2 Hz, 1H), 7.17(s, 1H), 7.12 (dd, J = 0.8, 8.1 Hz, 1H), 5.37 (s, 2H), 4.16 (t, J = 6.9Hz, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H), 1.82-1.75 (m, 2H),0.83 (t, J = 7.3 Hz, 3H) 434 (M⁺), 390, 172 (base) Example 12-6 Example11-4

(DMSO-d₆) δ: 9.85 (brs, 1H), 7.81 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),7.57 (d, J = 8.9 Hz, 1H), 7.34 (dd, J = 1.2, 8.9 Hz, 1H), 7.21 (s, 1H),7.13 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.25 (q, J = 7.3 Hz, 2H), 2.62(s, 3H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H), 1.32 (t, J = 7.3 Hz,3H) 434 (M⁺), 390, 216 (base) Example 12-8 Example 11-4

(DMSO-d₆) δ: 9.68 (brs, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H),7.48 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.39-7.36 (m, 1H),7.25 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 4.18 (q, J = 7.3 Hz, 2H), 2.55(s, 3H), 2.52 (s, 3H), 2.50 (s, 3H), 1.28 (t, J = 7.3 Hz, 3H) 454 (M⁺),410, 236 (base)

TABLE 117 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-3 Example 11-5

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.25 (dd, J = 1.9, 8.1 Hz, 1H), 7.77 (s,1H), 7.48-7.40 (m, 2H), 7.30-7.28 (m, 1H), 7.24 (d, J = 8.5 Hz, 1H),7.11-7.07 (m, 1H), 5.37 (s, 2H), 4.92 (s, 2H), 4.19-1.14 (m, 4H), 4.01(s, 3H), 2.49 (s, 3H) 406 (M⁺ − 44), 218 (base) Example 12-1 Example11-5

none 440 (M⁺ − 44), 252 (base) Example 12-6 Example 11-5

(DMSO-d₆) δ: 9.71 (brs, 1H), 7.77 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H),7.42 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.12(d, J = 8.1 Hz, 1H), 5.37 (s, 2H), 4.92 (s, 2H), 4.15 (brs, 4H), 2.50(s, 3H), 2.49 (s, 3H), 2.32 (s, 3H) 404 (M⁺ − 44), 216 (base) Example12-7 Example 11-5

(DMSO-d₆) δ: 9.71 (brs, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.76 (d, J = 8.5Hz, 1H), 7.42 (d, J = 8.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.25 (dd, J = 2.7,10.0 Hz, 1H), 7.15 (dt, J = 3.1, 8.9 Hz, 1H), 5.38 (s, 2H), 4.92 (s,2H), 4.15 (brs, 4H), 2.54 (s, 3H) 452 (M⁺), 408, 220 (base) Example 12-8Example 11-5

(DMSO-d₆) δ: 9.72 (brs, 1H), 7.78-7.75 (m, 2H), 7.48 (d, J = 2.3 Hz,1H), 7.42 (d, J = 8.5 Hz, 1H), 7.38 (dd, J = 2.3, 8.1 Hz, 1H), 7.29 (dd,J = 1.2, 8.5 Hz, 1H), 5.38 (s, 2H), 4.92 (s, 2H), 4.14 (brs, 4H), 2.55(s, 3H), 2.50 (s, 3H) 424 (M⁺ − 44), 215 (base)

TABLE 118 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-1 Example 11-6

(DMSO-d₆) δ: 9.61 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H),7.34 (d, J = 1.9 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.1 Hz,1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.36 (s, 2H), 4.08-4.03 (m, 2H),4.04 (s, 3H), 2.94-2.90 (m, 2H), 2.65-2.58 (m, 2H), 2.48 (s, 3H) 468(M⁺), 424, 269, 199 (base) Example 12-6 Example 11-6

(DMSO-d₆) δ: 9.64 (brs, 1H), 7.71 (s, 1H), 7.62 (d, J = 7.7 Hz, 1H),7.32 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 7.3 Hz, 1H), 7.17 (s, 1H), 7.12(d, J = 7.7 Hz, 1H), 5.36 (s, 2H), 4.10-4.03 (m, 2H), 2.95-2.90 (m, 2H),2.65-2.59 (m, 2H), 2.50 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H) 388 (M⁺ −44), 199 (base) Example 12-8 Example 11-6

(DMSO-d₆) δ: 9.66 (brs, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H),7.48 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 1.9, 8.1 Hz, 1H), 7.32 (d, J =8.1 Hz, 1H), 7.25-7.20 (m, 1H), 5.38 (s, 2H), 4.08-4.05 (m, 2H),2.94-2.91 (m, 2H), 2.65-2.59 (m, 2H), 2.55 (s, 3H), 2.50 (s, 3H) 452(M⁺), 408, 199 (base) Example 12-9 Example 11-6

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.22 (dd, J = 6.6, 8.9 Hz, 1H), 7.71 (s,1H), 7.66 (dd, J = 2.7, 8.9 Hz, 1H), 7.41-7.30 (m, 2H), 7.27-7.17 (m,1H), 5.39 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H), 2.94-2.91 (m, 2H),2.65-2.59 (m, 2H), 2.48 (s, 3H) 412 (M⁺ − 44), 199 (base) Example 12-1Example 11-7

(DMSO-d₆) δ: 9.62 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.69 (s, 1H),7.41-7.32 (m, 2H), 7.24-7.19 (m, 1H), 7.15 (dd, J = 1.9, 8.5 Hz, 1H),5.36 (s, 2H), 4.06-4.01 (m, 2H), 4.04 (s, 3H), 2.94-2.91 (m, 2H), 2.48(s, 3H), 2.05-1.99 (m, 2H), 1.94-1.88 (m, 2H) 269, 213 (base)

TABLE 119 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-5 Example 11-7

(DMSO-d₆) δ: 9.59 (brs, 1H), 8.18 (d, J = 8.9 Hz, 1H), 7.69 (s, 1H),7.33 (d, J = 8.9 Hz, 1H), 7.24-7.12 (m, 1H), 6.75 (d, J = 2.7 Hz, 1H),6.68 (dd, J = 2.3, 8.9 Hz, 1H), 5.33 (s, 2H), 4.06-4.03 (m, 2H), 4.00(s, 3H), 3.84 (s, 3H), 2.94-2.91 (m, 2H), 2.45 (s, 3H), 2.06-2.00 (m,2H), 1.94-1.88 (m, 2H) 434 (M⁺ − 44), 248 (base) Example 12-6 Example11-7

(DMSO-d₆) δ: 9.64 (brs, 1H), 7.69 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),7.32 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 7.17 (s, 1H), 7.12(d, J = 8.1 Hz, 1H), 5.36 (s, 2H), 4.06-4.03 (m, 2H), 2.94-2.91 (m, 2H),2.50 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H), 2.06-1.99 (m, 2H), 1.94-1.88(m, 2H) 446 (M⁺), 402, 216 (base) Example 12-7 Example 11-7

(DMSO-d₆) δ: 9.69 (brs, 1H), 7.77 (dd, J = 6.2, 8.9 Hz, 1H), 7.71 (s,1H), 7.36 (d, J = 8.5 Hz, 1H), 7.27-7.22 (m, 2H), 7.20-7.11 (m, 1H),5.38 (s, 2H), 4.07-4.04 (m, 2H), 2.96-2.93 (m, 2H), 2.54 (s, 3H), 2.50(s, 3H), 2.06-1.99 (m, 2H), 1.95-1.88 (m, 2H) 450 (M⁺), 406, 220 (base)Example 12-8 Example 11-7

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H),7.48 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 1.9, 8.1 Hz, 1H), 7.33 (d, J =8.5 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.06-4.03 (m, 2H),2.94-2.91 (m, 2H), 2.55 (s, 3H), 2.50 (s, 3H), 2.05-1.99 (m, 2H),1.94-1.88 (m, 2H) 422 (M⁺ − 44), 213 (base) Example 12-1 Example 11-9

(DMSO-d₆) δ: 9.61 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H),7.39 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 1.9 Hz, 1H), 7.27-7.20 (m, 1H),7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.36 (s, 2H), 4.60-4.58 (m, 1H), 4.04(s, 3H), 3.00-2.90 (m, 1H), 2.89-2.80 (m, 1H), 2.48 (s, 3H), 2.20-2.07(m, 1H), 2.07-1.95 (m, 1H), 1.95-1.82 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H)452 (M⁺ − 44), 212 (base)

TABLE 120 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-8 Example 11-9 

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H),7.48 (d, J = 2.3 Hz, 1H), 7.41-7.37 (m, 2H), 7.22 (d, J = 8.5 Hz, 1H),5.38 (s, 2H), 4.61-4.57 (m, 1H), 2.98-2.92 (m, 1H), 2.89-2.81 (m, 1H),2.55 (s, 3H), 2.50 (s, 3H), 2.16-2.08 (m, 1H), 2.03-1.95 (m, 1H),1.88-1.86 (m, 2H), 1.42 (d, J = 6.6 Hz, 3H) 480 (M⁺), 436, 236 (base)Example 12-9 Example 11-9 

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.22 (dd, J = 6.2, 8.9 Hz, 1H), 7.68-7.64(m, 2H), 7.42-7.37 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 5.39 (s, 2H),4.61-4.57 (m, 1H), 2.98-2.92 (m, 1H), 2.89-2.81 (m, 1H), 2.49 (s, 3H),2.16-2.07 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.83 (m, 2H), 1.41 (d, J =6.6 Hz, 3H) 484 (M⁺), 440, 200 (base) Example 12-8 Example 11-8 

(DMSO-d₆) δ: 9.63 (brs, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.68 (s, 1H),7.48 (d, J = 1.9 Hz, 1H), 7.40-7.37 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H),5.38 (s, 2H), 4.20-4.18 (m, 2H), 3.00-2.97 (m, 2H), 2.55 (s, 3H), 2.50(s, 3H), 1.88-1.84 (m, 2H), 1.72-1.65 (m, 2H) 480 (M⁺), 436, 227 (base)Example 12-9 Example 11-8 

(DMSO-d₆) δ: 9.64 (brs, 1H), 8.22 (dd, J = 6.6, 9.2 Hz, 1H), 7.67 (d, J= 2.7 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.42-7.37 (m, 2H), 7.22 (d, J =8.5 Hz, 1H), 5.39 (s, 2H), 4.19 (t, J = 5.0 Hz, 2H), 3.00-2.98 (m, 2H),2.48 (s, 3H), 1.87-1.84 (m, 2H), 1.73-1.65 (m, 2H) 484 (M⁺), 440, 200(base) Example 12-1 Example 11-10

(DMSO-d₆) δ: 9.73 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.96 (dd, J =0.8, 6.6 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.55 (dd, J = 2.7, 8.9 Hz,1H), 7.41-7.37 (m, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.16 (dd, J = 1.9, 8.5Hz, 1H), 5.37 (s, 2H), 4.04 (s, 3H), 4.00 (s, 3H), 2.49 (s, 3H) 398 (M⁺− 44), 252 (base)

TABLE 121 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-6 Example 11-10

(DMSO-d₆) δ: 9.76 (brs, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.62 (d, J = 8.1 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 1.5,8.9 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.38 (s, 2H), 4.00(s, 3H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H) 362 (M⁺ − 44), 216(base) Example 12-7 Example 11-10

(DMSO-d₆) δ: 9.76 (brs, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.76 (dd, J = 6.2, 8.9 Hz, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.41 (dd, J =1.9, 9.2 Hz, 1H), 7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.15 (dt, J = 2.7,8.5 Hz, 1H), 5.38 (s, 2H), 4.00 (s, 3H), 2.54 (s, 3H), 2.50 (s, 3H) 410(M⁺), 366, 220 (base) Example 12-7 Example 11-11

(DMSO-d₆) δ: 9.76 (brs, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.77 (dd, J = 6.2, 8.9 Hz, 1H), 7.59 (d, J = 9.2 Hz, 1H), 7.40 (dd, J =1.9, 8.9 Hz, 1H), 7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.15 (dt, J = 2.7,8.5 Hz, 1H), 5.39 (s, 2H), 4.39 (q, J = 7.3 Hz, 2H), 2.54 (s, 3H), 2.50(s, 3H), 1.38 (t, J = 7.3 Hz, 3H) 424 (M⁺), 380, 220 (base) Example 12-6Example 11-11

(DMSO-d₆) δ: 9.74 (brs, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.62 (d, J = 7.7 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 1.5,8.9 Hz, 1H), 7.17 (s, 1H), 7.12 (d, J = 8.5 Hz, 1H), 5.38 (s, 2H), 4.39(q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32 (s, 3H), 1.40-1.35(m, 3H) 420 (M⁺), 376, 216 (base) Example 12-1 Example 11-12

(DMSO-d₆) δ: 9.64 (brs, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.21 (s, 1H),7.84 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H), 7.21(dd, 1.9, 9.2 Hz, 1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.36 (s, 2H),4.12 (s, 3H), 4.04 (s, 3H), 2.48 (s, 3H) 442 (M⁺), 398, 252 (base)

TABLE 122 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-4 Example 11-12

(DMSO-d₆) δ: 9.63 (brs, 1H), 8.21 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H),7.84 (s, 1H), 7.50 (d, J = 9.2 Hz, 1H), 7.21 (d, J = 1.9, 9.2 Hz, 1H),7.06 (s, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.35 (s, 2H), 4.12 (s, 3H), 3.99(s, 3H), 2.47 (s, 3H), 2.37 (s, 3H) 378 (M⁺ − 44), 232 (base) Example12-6 Example 11-12

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.62 (d, J =8.1 Hz, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.22 (dd, J = 1.9, 8.9 Hz, 1H),7.17 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 5.37 (s, 2H), 4.12 (s, 3H), 2.50(s, 3H), 2.48 (s, 3H), 2.32 (s, 3H) 362 (M⁺ − 44), 216 (base) Example12-7 Example 11-12

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.76 (dd, J =6.3, 8.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.25 (dd, J = 2.9, 10.2 Hz,1H), 7.22 (dd, J = 1.9, 9.2 Hz, 1H), 7.17-7.12 (m, 1H), 5.38 (s, 2H),4.12 (s, 3H), 2.54 (s, 3H), 2.49 (s, 3H) 410 (M⁺), 366, 220 (base)Example 12-8 Example 11-12

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.21 (s, 1H), 7.84 (s, 1H), 7.76 (d, J =8.5 Hz, 1H), 7.51 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 1.9 Hz, 1H), 7.38(dd, J = 2.3, 8.5 Hz, 1H), 7.21 (dd, J = 1.9, 9.2 Hz, 1H), 5.38 (s, 2H),4.12 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H) 426 (M⁺), 382, 236 (base)Example 12-3 Example 11-13

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 1.5Hz, 1H), 7.86 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.46 (dt, J = 1.5, 8.5Hz, 1H), 7.27-7.20 (m, 2H), 7.11-7.07 (m, 1H), 5.37 (s, 2H), 4.40 (q, J= 7.3 Hz, 2H), 4.01 (s, 3H), 2.49 (s, 3H), 1.49 (t, J = 7.3 Hz, 3H) 422(M⁺), 378, 218 (base)

TABLE 123 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-4 Example 11-13

(DMSO-d₆) δ: 9.63 (brs, 1H), 8.25 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H),7.85 (s, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.22 (d, J = 1.9, 9.2 Hz, 1H),7.06 (s, 1H), 6.90 (d, J = 7.7 Hz, 1H), 5.35 (s, 2H), 4.40 (q, J = 7.3Hz, 2H), 3.99 (s, 3H), 2.47 (s, 3H), 2.37 (s, 3H), 1.49 (t, J = 7.3 Hz,3H) 392 (M⁺ − 44), 232 (base) Example 12-6 Example 11-13

(DMSO-d₆) δ: 9.67 (brs, 1H), 8.26 (d, J = 0.8 Hz, 1H), 7.85 (s, 1H),7.62 (d, J = 8.1 Hz, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.27-7.11 (m, 3H),5.37 (s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 2.50 (s, 3H), 2.49 (s, 3H), 2.32(s, 3H), 1.49 (t, J = 7.3 Hz, 3H) 420 (M⁺), 376, 216 (base) Example 12-7Example 11-13

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.26 (d, J = 0.8 Hz, 1H), 7.85 (s, 1H),7.76 (dd, J = 6.2, 8.9 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.27-7.21 (m,2H), 7.15 (dt, J = 2.7, 8.5 Hz, 1H), 5.38 (s, 2H), 4.40 (q, J = 7.3 Hz,2H), 2.54 (s, 3H), 2.49 (s, 3H), 1.49 (t, J = 7.3 Hz, 3H) 424 (M⁺), 380,220 (base) Example 12-8 Example 11-13

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.26 (s, 1H), 7.85 (s, 1H), 7.76 (d, J =8.5 Hz, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.49 (s, 1H), 7.38 (dd, J = 2.3,8.5 Hz, 1H), 7.22 (dd, J = 1.9, 9.2 Hz, 1H), 5.38 (s, 2H), 4.40 (q, J =7.3 Hz, 2H), 2.55 (s, 3H), 2.50 (s, 3H) 1.49 (t, J = 7.3 Hz, 3H) 440(M⁺), 396, 236 (base) Example 12-9 Example 11-13

(DMSO-d₆) δ: 9.68 (brs, 1H), 8.26 (s, 1H), 8.22 (dd, J = 6.3, 9.2 Hz,1H), 7.85 (s, 1H), 7.65 (dd, J = 2.4, 8.7 Hz, 1H), 7.52 (d, J = 9.2 Hz,1H), 7.42-7.37 (m, 1H), 7.22 (dd, J = 1.9, 9.2 Hz, 1H), 5.40 (s, 2H),4.40 (q, J = 7.2 Hz, 2H), 2.48 (s, 3H), 1.49 (t, J = 7.2 Hz, 3H) 444(M⁺), 400, 240 (base)

TABLE 124 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-10 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.17 (s, 1H), 7.87-7.86 (m, 1H), 7.80 (s,1H), 7.50 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.08 (d, J =3.1 Hz, 1H), 6.68 (dd, J = 1.9, 3.5 Hz, 1H), 5.35 (s, 2H), 4.23 (q, J =7.3 Hz, 2H), 2.45 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H) 382 (M⁺), 338, 178(base) Example 12-11 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.17 (s, 1H), 7.80 (s, 1H), 7.71 (dd, d =1.2, 5.0 Hz, 1H), 7.64 (dd, J = 1.2, 3.9 Hz, 1H), 7.50 (d, J = 8.5 Hz,1H), 7.31 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 3.9, 5.0 Hz, 1H), 5.34 (s,2H), 4.23 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H)398 (M⁺), 354, 194 (base) Example 12-12 Example 11-2

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.17 (s, 1H), 7.82 (d, J = 5.4 Hz, 1H),7.80 (s, 1H), 7.71 (dd, d = 1.2, 5.0 Hz, 1H), 7.64 (dd, J = 1.2, 3.9 Hz,1H), 7.50 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.24 (d, J =5.4 Hz, 1H), 5.39 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 2.47 (s, 3H), 1.40(t, J = 7.3 Hz, 3H) 432 (M⁺), 388, 228 (base) Example 12-10 Example 11-5

(DMSO-d₆) δ: 9.71 (brs, 1H), 7.87-7.86 (m, 1H), 7.76 (s, 1H), 7.42 (d, J= 8.9 Hz, 1H), 7.28 (d, J = 9.2 Hz, 1H), 7.08 (dd, J = 0.8, 3.5 Hz, 1H),6.69 (dd, J = 1.5, 3.5 Hz, 1H), 5.35 (s, 2H), 4.92 (s, 2H), 4.15 (s,4H), 2.45 (s, 3H) 407 (M⁺), 363, 203 (base) Example 12-12 Example 11-5

(DMSO-d₆) δ: 9.72 (brs, 1H), 7.82 (d, J = 5.4 Hz, 1H), 7.76 (s, 1H),7.42 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 6.9 Hz, 1H), 7.24 (d, J = 5.4 Hz,1H), 5.39 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H), 2.46 (s, 3H) 460 (M⁺),416, 215 (base)

TABLE 125 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-10 Example 11-7

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.87-7.86 (m, 1H), 7.69 (s, 1H), 7.33 (d, J= 8.9 Hz, 1H), 7.22 (d, J = 8.9 Hz, 1H), 7.08 (dd, J = 0.8, 3.5 Hz, 1H),6.69 (dd, J = 1.9, 3.5 Hz, 1H), 5.34 (s, 2H), 4.06-4.03 (m, 2H),2.94-2.91 (m, 2H), 2.45 (s, 3H), 2.04-1.99 (m, 2H), 1.94-1.90 (m, 2H)408 (M⁺), 364, 178 (base) Example 12-11 Example 11-7

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.71-7.00 (m, 2H), 7.64 (dd, J = 0.8, 3.5Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.9 Hz, 1H), 7.15 (dd, J= 3.5, 5.0 Hz, 1H), 5.33 (s, 2H), 4.04 (t, J = 6.2 Hz, 2H), 2.94-2.91(m, 2H), 2.43 (s, 3H), 2.04-1.99 (m, 2H), 1.94-1.90 (m, 2H) 380 (M⁺ −44), 194 (base) Example 12-13 Example 11-2

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.46 (dd, J = 1.2, 4.6 Hz, 1H), 8.17 (s,1H), 7.80-7.77 (m, 2H), 7.50 (d, J = 8.9 Hz, 1H), 7.37 (dd, J = 4.6, 7.7Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 5.37 (s, 2H), 4.23 (q, J = 7.3 Hz,2H), 2.73 (s, 3H), 2.50 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H) 407 (M⁺), 363,203 (base) Example 12-13 Example 11-5

(DMSO-d₆) δ: 9.71 (brs, 1H), 8.47-8.46 (m, 1H), 7.79-7.77 (m, 2H), 7.42(d, J = 8.5 Hz, 1H), 7.37 (dd, J = 5.0, 7.7 Hz, 1H), 7.29 (d, J = 8.5Hz, 1H), 5.37 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H), 2.73 (s, 3H), 2.50(s, 3H) 435 (M⁺), 391, 203 (base) Example 12-14 —

(DMSO-d₆) δ: 9.69 (brs, 1H), 8.28 (dd, J = 1.9, 8.1 Hz, 1H), 8.11 (s,1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.50-7.45 (m, 2H), 7.33 (d, J = 8.1 Hz,1H), 7.26 (d, J = 8.5 Hz, 1H), 7.13-7.09 (m, 1H), 5.43 (s, 2H), 4.02 (s,3H), 3.80 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H) 350 (M⁺ − 44), 173 (base)

TABLE 126 Hydroxy Carboxylic compound acid Example ¹H-NMR Mass, m/zExample 12-15 —

(DMSO-d₆) δ: 9.66 (brs, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H),7.80 (s, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.32(d, J = 8.5 Hz, 1H), 7.17 (dd, J = 1.5, 8.5 Hz, 1H), 5.38 (s, 2H), 4.04(s, 3H), 3.80 (s, 3H), 2.84 (q, J = 7.3 Hz, 2H), 1.28 (t, J = 7.3 Hz,3H) 412 (M⁺ − 44), 283, 173 (base) Example 12-16 —

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.10 (s, 1H),7.80 (s, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.35 (d, J = 1.9 Hz, 1H),7.34-7.30 (m, 1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 5.38 (s, 2H), 4.04(s, 3H), 3.80 (s, 3H), 2.80 (q, J = 7.3 Hz, 2H), 1.73 (sextet, J = 7.3Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H) 426 (M⁺ − 44), 297, 173 (base) Example12-20 4-Fluoro benzoic acid

(DMSO-d₆) δ: 9.81 (brs, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.51-7.44 (m,2H), 7.34-7.32 (m, 1H), 7.20-7.11 (m, 2H), 7.04 (dd, J = 1.9, 8.5 Hz,1H), 6.82 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H) 389 (M⁺),343, 248, 235, 111 (base) Example 12-19 4-Methoxy benzoic acid

(DMSO-d₆) δ: 9.57 (brs, 1H), 7.84 (dd, J = 7.38, 5 Hz, 1H), 7.36 (d, J =8.5 Hz, 2H), 6.99 (dd, J = 2.3, 11.6 Hz, 1H), 6.87 (d, J = 9.2 Hz, 2H),6.80 (dt, J = 2.3, 8.5 Hz, 1H), 6.77 (s, 1H), 5.21 (s, 2H), 3.90 (s,3H), 3.87 (s, 3H), 3.71 (s, 3H) 385 (M⁺), 341, 236, 219 (base), 178

TABLE 127 Hydroxy Mass, compound Carboxylic acid Example ¹H-NMR m/zExample 12-20 3-Fluoro-4- methoxy- benzoic acid

(DMSO-d₆) δ: 9.78 (br s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.37 (d, J =13.7 Hz, 1H), 7.15 (dd, J = 1.5, 8.1 Hz, 1H), 7.12-7.08 (m, 1H), 7.04(dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.24 (s, 2H), 3.91 (s, 3H),3.89 (s, 3H), 3.79 (s, 3H) 419 (M⁺),  375, 235 (base) Example 12-173-Fluoro-4- methoxy- benzoic acid

(DMSO-d₆) δ: 9.77 (br s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.37 (d, J =13.1 Hz, 1H), 7.19-7.08 (m, 2H), 6.91 (s, 1H), 6.80-6.78 (m, 2H), 5.23(s, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.79 (s, 3H) 399 (M⁺),  355,  248,215 (base) Example 12-20 3-Dihydro- 1-benzofuran- 5-carboxylic acid

(DMSO-d₆) δ: 9.50 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H),7.16 (d, J = 1.9 Hz, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.03 (dd, J = 2.3,8.5 Hz, 1H), 6.81 (s, 1H), 6.67 (d, J = 8.5 Hz, 1H), 5.21 (s, 2H), 4.48(t, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.14 (t, J = 8.5 Hz,3H) 413 (M⁺),  399, 235 (base) Example 12-17 2,3-Dihydro- 1-benzofuran-5-carboxylic acid

(DMSO-d₆) δ: 9.50 (br s, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.34 (s, 1H),7.11 (d, J = 8.5 Hz, 1H), 6.90 (s, 1H), 6.78 (dd, J = 0.8, 8.5 Hz, 1H),6.77 (s, 1H), 6.67 (d, J = 8.9 Hz, 1H), 5.20 (s, 2H), 4.48 (t, J = 8.5Hz, 2H), 3.89 (s, 3H), 3.84 (s, 3H), 3.14 (t, J = 8.5 Hz, 3H), 2.32 (s,3H) 393 (M⁺),  349, 215 (base)

TABLE 128 Hydroxy Mass, compound Carboxylic acid Example ¹H-NMR m/zExample 12-20 Benzoxazole-6- carboxylic acid

(DMSO-d₆) δ: 10.08 (br s, 1H), 8.63 (s, 1H), 7.99 (d, J = 0.8 Hz, 1H),7.86 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 1.9,8.5 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H),6.85 (s, 1H), 5.28 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H) 412 (M⁺),  368, 235, 160 (base) Example 12-21 —

(DMSO-d₆) δ: 9.70 (br s, 1H), 8.11 (s, 1H), 7.86 (dd, J = 1.9, 7.7 Hz,1H), 7.81 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.33- 7.30 (m, 1H), 7.28(dd, J = 1.9, 7.3 Hz, 1H), 7.09 (dd, J = 0.8, 8.5 Hz, 1H), 6.97 (dt, J =1.2, 7.3 Hz, 1H), 6.84 (s, 1H), 5.26 (s, 2H), 3.93 (s, 3H), 3.85 (s,3H), 3.80 (s, 3H) 391 (M⁺),  347, 173 (base) Example 12-22 —

(DMSO-d₆) δ: 9.68 (s, 1H), 8.11 (s, 1H), 7.87 (dd, J = 1.9, 7.7 Hz, 1H),7.81 (s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.33-7.27 (m, 2H), 7.09 (d, J =7.7 Hz, 1H), 7.00- 6.96 (m, 1H), 6.83 (s, 1H), 5.27 (s, 2H), 4.24 (q, J= 7.3 Hz, 2H), 3.86 (s, 3H), 3.80 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 405(M⁺),  232,  215, 173 (base) Example 12-21 Example 11-2

(DMSO-d₆) δ: 9.69 (br s, 1H), 8.17 (s, 1H), 7.86 (dd, J = 1.5, 7.7 Hz,1H), 7.81 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.32- 7.26 (m, 2H), 7.09(d, J = 7.7 Hz, 1H), 6.99-6.95 (m, 1H), 6.83 (s, 1H), 5.26 (s, 2H), 4.23(q, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.85 (s, 3H), 1.40 (t, J = 7.3 Hz,3H) 405 (M⁺),  361, 201 (base), 187

TABLE 129 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-22 Example 11-2

(DMSO-d₆) δ: 9.68 (br s, 1H), 8.18 (s, 1H), 7.87 (dd, J = 1.9, 7.7 Hz,1H), 7.81 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.32- 7.27 (m, 2H), 7.09(d, J = 7.7 Hz, 1H), 6.98 (dt, J = 0.8, 7.7 Hz, 1H), 6.83 (s, 1H), 5.27(s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.23 (q, J = 7.3 Hz, 2H), 3.86 (s,3H), 1.44-1.38 (m, 6H) 419 (M⁺),  375,  232, 187 (base) Example 12-19 —

(DMSO-d₆) δ: 9.70 (s, 1H), 8.11 (s, 1H), 7.87-7.81 (m, 2H), 7.47 (d, J =8.9 Hz, 1H), 7.32 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 2.7, 11.6 Hz, 1H),6.83-6.78 (m, 2H), 5.25 (s, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 3.80 (s,3H) 409 (M⁺),  365,  236, 219 (base) Example 12-24 —

(DMSO-d₆) δ: 9.68 (br s, 1H), 8.11 (s, 1H), 7.86 (dd, J = 7.3, 8.5 Hz,1H), 7.81 (s, 1H), 7.46 (dd, J = 2.3, 11.6 Hz, 1H), 6.82 (dd, J = 2.7,8.5 Hz, 1H), 6.78 (s, 1H), 5.26 (s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 3.87(s, 3H), 3.80 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H) 423 (M⁺),  379,  250,233 (base) Example 12-19 Example 11-2

(DMSO-d₆) δ: 9.69 (br s, 1H), 8.17 (s, 1H), 7.85 (dd, J = 6.9, 8.5 Hz,1H), 7.81 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 0.8, 8.5 Hz,1H), 6.99 (dd, J = 2.3, 11.6 Hz, 1H), 6.80 (dt, J = 2.3, 8.5 Hz, 1H),6.79 (s, 1H), 5.25 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 3.92 (s, 3H), 3.87(s, 3H), 1.40 (t, J = 7.3 Hz, 3H) 423 (M⁺),  379,  236, 187 (base), 172

TABLE 130 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-24 Example 11-2

(DMSO-d₆) δ: 9.67 (br s, 1H), 8.17 (s, 1H), 7.86 (dd, J = 6.9, 8.5 Hz,1H), 7.81 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H),6.99 (dd, J = 2.3, 11.6 Hz, 1H), 6.81 (dd, J = 2.7, 8.5 Hz, 1H), 6.78(s, 1H), 5.26 (s, 2H), 4.26- 4.20 (m, 4H), 3.87 (s, 3H), 1.43-1.20 (m,6H) 437 (M⁺),  393,  250,  233, 187 (base) Example 12-20 —

(DMSO-d₆) δ: 9.71 (br s, 1H), 8.12 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H),7.81 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.17(d, J = 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.84 (s, 1H), 5.25(s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.80 (s, 3H) 381 (M⁺ −    44), 173(base) Example 12-33 —

(DMSO-d₆) δ: 9.68 (s, 1H), 8.11 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.80(s, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.16 (d, J= 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.26 (s,2H), 4.24 (q, J = 7.3 Hz, 2H), 3.90 (s, 3H), 3.80 (s, 3H), 1.42 (t, J =7.3 Hz, 3H) 439 (M⁺),  395,  266,  249, 173 (base) Example 12-20 Example11-2

(DMSO-d₆) δ: 9.69 (s, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.80(s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (d, J= 5.3 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.25 (s, 2H),4.23 (q, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.40 (t, J = 7.3Hz, 3H) 439 (M⁺),  395,  252, 187 (base)

TABLE 131 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-33 Example 11-2

(DMSO-d₆) δ: 9.67 (br s, 1H), 8.17 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H),7.81 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.16(d, J = 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.27(s, 2H), 4.27-4.20 (m, 4H), 3.89 (s, 3H), 1.44-1.38 (m, 6H) 453 (M⁺), 409,  266, 187 (base), 172 Example 12-17 —

(DMSO-d₆) δ: 9.68 (br s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.73 (d, J =7.7 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.79(s, 1H), 6.79-6.78 (m, 1H), 5.24 (s, 2H), 3.91 (s, 3H), 3.84 (s, 3H),3.80 (s, 3H), 2.32 (s, 3H) 405 (M⁺),  361, 173 (base) Example 12-23 —

(DMSO-d₆) δ: 9.67 (s, 1H), 8.11 (s, 1H), 7.81 (s, 1H), 7.75 (d, J = 7.7Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 6.91 (s,1H), 6.79 (d, J = 8.5 Hz, 1H), 6.79 (s, 1H), 5.25 (s, 2H), 4.23 (q, J =7.3 Hz, 2H), 3.84 (s, 3H), 3.80 (s, 3H), 2.33 (s, 3H), 1.41 (t, J = 7.3Hz, 3H) 419 (M⁺),  375,  246,  229, 173 (base) Example 12-17 Example11-2

(DMSO-d₆) δ: 9.64 (br s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.73 (d, J =8.1 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 0.8, 8.1 Hz, 1H),6.91 (s, 1H), 6.79-6.77 (m, 2H), 5.24 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H),3.91 (s, 3H), 3.84 (s, 3H), 2.32 (s, 3H), 1.40 (t, J = 7.3 Hz, 3H) 419(M⁺),  375,  232,  215, 187 (base)

TABLE 132 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-23 Example 11-2 

(DMSO-d₆) δ: 9.66 (br s, 1H), 8.17 (s, 1H), 7.81 (s, 1H), 7.75 (d, J =8.1 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1H), 6.91(s, 1H), 6.79 (d, J = 8.9 Hz, 1H), 6.78 (s, 1H), 5.25 (s, 2H), 4.23 (q,J = 7.3 Hz, 4H), 3.84 (s, 3H), 2.33 (s, 3H), 1.43-1.38 (m, 6H) 433 (M⁺), 389,  246,  187, 172 (base) Example 12-34 Example 11-2 

(DMSO-d₆) δ: 9.71 (br s, 1H), 8.71 (s, 1H), 7.81 (s, 1H), 7.51 (d, J =8.9 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.32-7.30 (m, 1H), 7.07 (s, 1H),7.03 (d, J = 8.1 Hz, 1H), 6.59 (s, 1H), 5.26 (s, 2H), 4.23 (q, J = 7.3Hz, 2H), 3.93 (s, 3H), 2.40 (s, 3H), 2.28 (s, 3H), 1.40 (t, J = 7.3 Hz,3H) 403 (M⁺),  359,  216, 187 (base) Example 12-17 Example 11-15

(DMSO-d₆) δ: 9.70 (br s, 1H), 8.76 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H),7.46 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (d, J = 1.9 Hz,1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.83 (m, 1H), 6.23 (s, 1H), 5.25(s, 2H), 4.66 (s, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.77 (s, 3H), 3.32(s, 3H) 469 (M⁺),  325, 172 (base) Example 12-20 Example 11-14

(DMSO-d₆) δ: 9.69 (br s, 1H), 8.11 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H),7.80 (s, 1H), 7.51 (d, J = 8.9 Hz, 1H), 7.29 (d, J = 7.3 Hz, 1H), 7.16(d, J = 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.84 (s, 1H), 5.27(s, 2H), 4.36 (t, J = 5.1 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 3.66 (t,J = 5.1 Hz, 2H), 3.22 (s, 3H) 469 (M⁺),  425,  252,  217, 172 (base)Example 12-21 Example 11-5 

(DMSO-d₆) δ: 9.70 (s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz, 1H), 7.77 (s, 1H),7.42 (d, J = 8.5 Hz, 1H), 7.31-7.26 (m, 2H), 7.09 (d, J = 7.7 Hz, 1H),6.99-6.95 (m, 1H), 6.84 (s, 1H), 5.25 (s, 2H), 4.92 (s, 2H), 4.15 (s,4H), 3.92 (s, 3H), 3.85 (s, 3H) 433 (M⁺),  389,  215, 201 (base)

TABLE 133 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-22 Example 11-5

(DMSO-d₆) δ: 9.68 (br s, 1H), 7.87 (dd, J = 1.5, 7.7 Hz, 1H), 7.77 (s,1H), 7.42 (d, J = 8.9 Hz, 1H), 7.31-7.27 (m, 2H), 7.09 (d, J = 8.1 Hz,1H), 6.97 (t, J = 7.3 Hz, 1H), 6.82 (s, 1H), 5.26 (s, 2H), 4.92 (s, 2H),4.24 (q, J = 7.3 Hz, 2H), 4.15 (s, 4H), 3.86 (s, 3H), 1.42 (t, J = 7.3Hz, 3H) 403 (M⁺ −    44),  232, 215 (base) Example 12-19 Example 11-5

(DMSO-d₆) δ: 9.70 (s, 1H), 7.85 (dd, J = 7.3, 8.5 Hz, 1H), 7.76 (s, 1H),7.42 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 2.3,11.6 Hz, 1H), 6.81-6.78 (m, 1H), 6.79 (s, 1H), 5.24 (s, 2H), 4.91 (s,2H), 4.15 (s, 4H), 3.92 (s, 3H), 3.87 (s, 3H) 451 (M⁺),  407,  236, 215(base) Example 12-24 Example 11-5

(DMSO-d₆) δ: 9.68 (s, 1H), 7.88-7.84 (m, 1H), 7.77 (s, 1H), 7.42 (d, J =8.5 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 6.99 (dd, J = 2.7, 11.6 Hz, 1H),6.81-6.79 (m, 1H), 6.78 (s, 1H), 5.26 (s, 2H), 4.92 (s, 2H), 4.23 (q, J= 7.3 Hz, 2H), 4.15 (s, 4H), 3.87 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 465(M⁺),  421,  250, 215 (base) Example 12-20 Example 11-5

(DMSO-d₆) δ: 9.70 (br s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.77 (s, 1H),7.42 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.16 (d, J = 2.3 Hz,1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.25 (s, 2H), 4.92(s, 2H), 4.15 (s, 4H), 3.93 (s, 3H), 3.89 (s, 3H) 467 (M⁺),  424,  252,215 (base)

TABLE 134 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-33 Example 11-5

(DMSO-d₆) δ: 9.68 (br s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H),7.42 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.16,(d, J = 2.3 Hz,1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.26 (s, 2H), 4.92(s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.15 (s, 4H), 3.89 (s, 3H), 1.42 (t,7.3 Hz, 3H) 481 (M⁺),  437,  266, 249 (base) Example 12-17 Example 11-5

(DMSO-d₆) δ: 9.70 (br s, 1H), 7.77 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H),7.42 (d, J = 8.9 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.90 (s, 1H), 6.79(s, 1H), 6.78 (d, J = 5.4 Hz, 1H), 5.24 (s, 2H), 4.92 (s, 2H), 4.15 (s,4H), 3.91 (s, 3H), 3.84 (s, 3H), 2.32 (s, 3H) 447 (M⁺),  403,  232, 215(base) Example 12-23 Example 11-5

(DMSO-d₆) δ: 9.67 (br s, 1H), 7.77- 7.74 (m, 2H), 7.42 (d, J = 8.5 Hz,1H), 7.29 (d, J = 9.2 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J = 9.6 Hz, 1H),6.78 (s, 1H), 5.25 (s, 2H), 4.92 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.15(s, 4H), 3.84 (s, 3H), 2.33 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H) noneExample 12-34 Example 11-5

(DMSO-d₆) δ: 9.72 (br s, 1H), 7.80 (br s, 1H), 7.44-7.40 (m, 2H),7.30-7.27 (m, 1H), 7.06 (s, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.59 (s, 1H),5.26 (s, 2H), 4.92 (s, 2H), 4.15 (s, 4H), 3.92 (s, 3H), 2.41 (s, 3H),2.28 (s, 3H) 431 (M⁺),  387, 215 (base), 185 Example 12-25 Example 11-5

(DMSO-d₆) δ: 9.72 (s, 1H), 7.79 (s, 1H), 7.45-7.41 (m, 2H), 7.29 (dd, J= 1.2, 8.5 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.58 (s,1H), 5.27 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 4.93 (s, 2H), 4.15 (s, 4H),2.42 (s, 3H), 2.29 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H) 445 (M⁺),  401, 230, 215 (base)

TABLE 135 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-21 Example 11-6

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz, 1H), 7.71 (brs, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.29 (dd, J = 1.9, 7.3 Hz, 1H),7.28-7.26 (m, 1H), 7.08 (d, J = 7.3 Hz, 1H), 6.99-6.95 (m, 1H), 6.83 (s,1H), 5.24 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 3H),2.92 (t, J = 7.3 Hz, 2H), 2.61 (quint, J = 7.3 Hz, 2H) 417 (M⁺),  373, 218, 199 (base) Example 12-19 Example 11-6

(DMSO-d₆) δ: 9.63 (br s, 1H), 7.85 (dd, J = 7.3, 8.5 Hz, 1H), 7.71 (s,1H), 7.31 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.98 (dd, J =2.7, 11.6 Hz, 1H), 6.79 (s, 1H), 6.82- 6.77 (m, 1H), 5.24 (s, 2H), 4.07(t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.93 (t, J = 7.3 Hz,2H), 2.62 (quint, J = 7.3 Hz, 2H) 435 (M⁺),  391,  236, 199 (base)Example 12-24 Example 11-6

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.86 (dd, J = 7.3, 8.5 Hz, 1H), 7.71 (s,1H), 7.32 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.99 (dd, J =2.3, 11.6 Hz, 1H), 6.81 (dt, J = 2.3, J = 8.5 Hz, 1H), 6.78 (s, 1H),5.25 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.06 (t, J = 6.9 Hz, 2H), 3.87(s, 3H), 2.92 (t, J = 7.3 Hz, 2H), 2.61 (quint, J = 7.3 Hz, 2H), 1.42(t, J = 7.3 Hz, 3H) 449 (M⁺),  405,  233, 199 (base) Example 12-20Example 11-6

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H),7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 9.3 Hz, 1H), 7.16 (d, J = 1.9 Hz,1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.83 (s, 1H), 5.24 (s, 2H), 4.07(t, J = 7.3 Hz, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 2.92 (t, J = 7.3 Hz,2H), 2.61 (quint, J = 7.3 Hz, 2H) 451 (M⁺),  407,  252, 199 (base)

TABLE 136 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-33 Example 11-6

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H),7.32 (d, J = 8.9 Hz, 1H), 7.22-7.20 (m, 2H), 7.16 (d, J = 1.9 Hz, 1H),6.81 (s, 1H), 5.25 (s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.06 (t, J = 6.9Hz, 2H), 3.89 (s, 3H), 2.92 (t, J = 7.3 Hz, 2H), 2.61 (quint, J = 7.3Hz, 2H), 1.42 (t, J = 7.3 Hz, 3H) 465 (M⁺),  421,  266, 199 (base)Example 12-34 Example 11-6

(DMSO-d₆) δ: 9.65 (br s, 1H), 7.71 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H),7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.06-7.01 (m, 2H),6.59 (s, 1H), 5.25 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H), 3.92 (s, 3H), 2.93(t, J = 7.3 Hz, 2H), 2.64-2.60 (m, 2H), 2.41 (s, 3H), 2.28 (s, 3H) 415(M⁺),  371,  216, 199 (base) Example 12-25 Example 11-6

(DMSO-d₆) δ: 9.63 (br s, 1H), 7.72 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H),7.32 (d, J = 8.5 Hz, 1H), 7.23-7.21 (m, 1H), 7.07-7.02 (m, 2H), 6.58 (s,1H), 5.26 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H),2.93 (t, J = 7.3 Hz, 2H), 2.63-2.60 (m, 2H), 2.42 (s, 3H), 2.29 (s, 3H),1.43 (t, J = 7.3 Hz, 3H) 429 (M⁺),  385,  230, 199 (base) Example 12-17Example 11-6

(DMSO-d₆) δ: 9.63 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H), 7.32(d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.9 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J= 7.3 Hz, 1H), 6.79 (s, 1H), 5.23 (s, 2H), 4.07 (t, J = 6.9 Hz, 2H),3.91 (s, 3H), 3.84 (s, 3H), 2.92 (t, J = 7.3 Hz, 2H), 2.61 (quint, J =7.3 Hz, 2H), 2.32 (s, 3H) 431 (M⁺),  387,  232,  215, 199 (base) Example12-23 Example 11-6

(DMSO-d₆) δ: 9.61 (br s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.71 (s, 1H),7.32 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 8.1 Hz, 1H), 6.90 (s, 1H), 6.79(dd, J = 0.8, 7.7 Hz, 1H), 6.77 (s, 1H), 5.24 (s, 2H), 4.23 (q, J = 7.3Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H), 3.84 (s, 3H), 2.92 (t, J = 7.3 Hz,2H), 2.62 (t, J = 7.7 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H)445 (M⁺),  401,  246, 199 (base)

TABLE 137 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-21 Example 11-7

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.85 (dd, J = 1.9, 7.7 Hz, 1H), 7.70 (s,1H), 7.34 (d, J = 8.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.23 (d, J = 8.9 Hz,1H), 7.09 (d, J = 7.7 Hz, 1H), 6.97 (dt, J = 1.2, 7.7 Hz, 1H), 6.83 (s,1H), 5.24 (s, 2H), 4.06-4.03 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 2.92(t, J = 6.2 Hz, 2H), 2.06-1.99 (m, 2H), 1.94- 1.88 (m, 2H) 431 (M⁺), 387, 213 (base) Example 12-22 Example 11-7

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.87 (dd, J = 1.9, 7.7 Hz, 1H), 7.70 (s,1H), 7.34 (d, J = 8.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.23 (d, J = 8.1 Hz,1H), 7.09 (d, J = 8.5 Hz, 1H), 6.98 (dt, J = 1.2, 7.7 Hz, 1H), 6.82 (s,1H), 5.25 (s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.06-4.01 (m, 2H), 3.86 (s,3H), 2.94-2.91 (m, 2H), 2.06-1.99 (m, 2H), 1.94-1.88 (m, 2H), 1.42 (t, J= 7.3 Hz, 3H) 445 (M⁺),  401, 213 (base) Example 12-19 Example 11-7

(DMSO-d₆) δ: 9.64 (br s, 1H), 7.85 (dd, J = 7.3, 8.5 Hz, 1H), 7.70 (s,1H), 7.34 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 6.99 (dd, J =2.3 Hz, 11.2 Hz, 1H), 6.80 (dt, J = 2.3, 8.5 Hz, 1H), 6.79 (s, 1H), 5.24(s, 2H), 4.06-4.03 (m, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.94-2.91 (m,2H), 2.06-1.99 (m, 2H), 1.94- 1.88 (m, 2H) 449 (M⁺),  405, 213 (base)Example 12-24 Example 11-7

(DMSO-d₆) δ: 9.62 (br s, 1H), 7.86 (dd, J = 6.9, 8.5 Hz, 1H), 7.70 (s,1H), 7.34 (d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.99 (dd, J =2.3 Hz, 11.2 Hz, 1H), 6.81 (dt, J = 2.3, 8.5 Hz, 1H), 6.78 (s, 1H), 5.25(s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.87 (s,3H), 2.92 (t, J = 6.2 Hz, 2H), 2.04-1.99 (m, 2H), 1.94- 1.90 (m, 2H),1.42 (t, J = 7.3 Hz, 3 H) 463 (M⁺),  419, 213 (base)

TABLE 138 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-20 Example 11-7

(DMSO-d₆) δ: 9.64 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.34(d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 1.9 Hz, 1H),7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.83 (s, 1H), 5.24 (s, 2H), 4.04 (t, J =6.2 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.92 (t, J = 6.2 Hz, 2H),2.04-2.01 (m, 2H), 1.93-1.90 (m, 2H) 421 (M⁺),  252, 213 (base) Example12-33 Example 11-7

(DMSO-d₆) δ: 9.61 (s, 1H), 7.88 (d, J = 8.5 Hz, 1H), 7.70 (s, 1H), 7.34(d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H),7.04 (dd, J = 2.3, 8.5 Hz, 1H), 6.82 (s, 1H), 5.25 (s, 2H), 4.24 (q, J =7.3 Hz, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 2.93 (t, J = 6.2Hz, 2H), 2.04-2.01 (m, 2H), 2.00- 1.90 (m, 2H), 1.42 (t, J = 6.9 Hz, 3H)479 (M⁺),  435,  266, 213 (base), 185 Example 12-17 Example 11-7

(DMSO-d₆) δ: 9.63 (s, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H), 7.34(d, J = 8.9 Hz, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.91 (s, 1H), 6.80- 6.78(m, 2H), 5.23 (s, 2H), 4.04 (t, J = 6.2 Hz, 2H), 3.91 (s, 3H), 3.84 (s,3H), 2.92 (t, J = 6.2 Hz, 2H), 2.32 (s, 3H), 2.04-2.00 (m, 2H), 1.93-1.90 (m, 2H) 401 (M⁺ −    44),  232 , 213 (base) Example 12-23 Example11-7

(DMSO-d₆) δ: 9.61 (br s, 1H), 7.74 (d, J = 7.7 Hz, 1H), 7.70 (s, 1H),7.33 (d, J = 8.9 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 6.91 (s, 1 H), 6.80(s, 1H), 6.77 (s, 1H), 5.24 (s, 2H), 4.22 (q, J = 7.3 Hz, 2H), 4.04 (t,J = 7.3 Hz, 2H), 3.84 (s, 3H), 2.94-2.91 (m, 2H), 2.33 (s, 3H),2.04-1.99 (m, 2H), 1.94-1.90 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H) 459 (M⁺), 415, 213 (base)

TABLE 139 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-34 Example 11-7 

(DMSO-d₆) δ: 9.66 (s, 1H), 7.71 (s, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.34(d, J = 8.5 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.06 (s, 1H), 7.02 (d, J= 7.7 Hz, 1H), 6.59 (s, 1H), 5.24 (s, 2H), 4.05 (t, J = 6.2 Hz, 2H),3.93 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H), 2.28 (s, 3H),2.04-2.00 (m, 2H), 1.93-1.89 (m, 2H) 429 (M⁺),  385, 213 (base), 185Example 12-25 Example 11-7 

(DMSO-d₆) δ: 9.64 (s, 1H), 7.71 (s, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.34(d, J = 8.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.07 (s, 1H), 7.03 (d, J= 7.7 Hz, 1H), 6.58 (s, 1H), 5.26 (s, 2H), 4.23 (q, J = 6.9 Hz, 2H),4.05 (t, J = 6.2 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H), 2.41 (s, 3H), 2.28(s, 3H), 2.06-2.00 (m, 2H), 1.94- 1.89 (m, 2H), 1.43 (t, J = 6.9 Hz, 3H)443 (M⁺),  399,  230, 213 (base) Example 12-22 Example 11-10

(DMSO-d₆) δ: 9.73 (br s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.87 (dd, J = 1.9, 7.7 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.41 (dd, J =1.5, 8.9 Hz, 1H), 7.31-7.27 (m, 1H), 7.09 (d, J = 7.7 Hz, 1H), 6.98 (dt,J = 0.8, 7.7 Hz, 1H), 6.82 (s, 1H), 5.27 (s, 2H), 4.24 (q, J = 7.3 Hz,2H), 4.04 (s, 3H), 3.86 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H) 405 (M⁺), 361, 215 (base), 173 Example 12-19 Example 11-10

(DMSO-d₆) δ: 9.75 (br s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.85 (dd, J = 6.9, 8.9 Hz, 1H), 7.56 (d, J = 9.3 Hz, 1H), 7.41 (dd, J =1.9, 8.9 Hz, 1H), 6.99 (dd, J = 2.3, 11.6 Hz, 1H), 6.80 (dt, J = 2.3,8.5 Hz, 1H), 6.79 (s, 1H), 5.25 (s, 2H), 4.00 (s, 3H), 3.92 (s, 3H),3.87 (s, 3H) 409 (M⁺),  365,  236, 219 (base), 173

TABLE 140 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-24 Example 11-10

(DMSO-d₆) δ: 9.73 (br s, 1H), 7.97 (s, 1H), 7.88-7.84 (m, 2H), 7.56 (d,J = 9.3 Hz, 1H), 7.41 (dd, J = 1.5, 9.3 Hz, 1H), 6.99 (dd, J = 2.7, 11.6Hz, 1H), 6.81 (dt, J = 2.7, 8.5 Hz, 1H), 6.78 (s, 1H), 5.26 (s, 2H),4.23 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 3.87 (s, 3H), 1.42 (t, J = 7.3Hz, 3H) 423 (M⁺),  379, 233 (base), 178 Example 12-20 Example 11-10

(DMSO-d₆) δ: 9.74 (br s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (d, J = 1.2Hz, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.41 (dd, J= 1.5, 8.9 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz,1H), 6.83 (s, 1H), 5.25 (s, 2H), 4.00 (s, 3H), 3.93 (s, 3H), 3.89 (s,3H) 425 (M⁺),  381,  235, 173 (base) Example 12-33 Example 11-10

(DMSO-d₆) δ: 9.73 (br s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.88 (d, J = 8.5Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 1.5, 8.9 Hz, 1H), 7.17(d, J = 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H), 6.82 (s, 1H), 5.27(s, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 3.89 (s, 3H), 1.42 (t,J = 7.3 Hz, 3H) 425 (M⁺),  381,  235, 173 (base) Example 12-20 Example11-11

(DMSO-d₆) δ: 9.74 (br s, 1H), 7.98 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.86 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.39 (dd, J = 1.5,8.9 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 7.04 (dd, J = 1.9, 8.5 Hz, 1H),6.84 (s, 1H), 5.26 (s, 2H), 4.39 (q, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.89(s, 3H), 1.38 (t, J = 7.3 Hz, 3H) 439 (M⁺),  395, 172 (base)

TABLE 141 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-23 Example 11-10

(DMSO-d₆) δ: 9.72 (br s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H),7.74 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 8.9 Hz, 1H), 7.41 (dd, J = 1.5,8.9 Hz, 1H), 6.91 (s, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.78 (s, 1H), 5.25(s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.00 (s, 3H), 3.84 (s, 3H), 2.33 (s,3H), 1.41 (t, J = 7.3 Hz, 3H) 419 (M⁺),  375, 229 (base), 174 Example12-34 Example 11-10

(DMSO-d₆) δ: 9.77 (s, 1H), 7.97 (d, J = 0.8 Hz, 1H), 7.89 (s, 1H), 7.56(d, J = 8.9 Hz, 1H), 7.42-7.40 (m, 2H), 7.06 (s, 1H), 7.02 (d, J = 8.1Hz, 1H), 6.59 (s, 1H), 5.26 (s, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 2.40(s, 3H), 2.28 (s, 3H) 389 (M⁺),  345,  199,  173, 158 (base) Example12-25 Example 11-10

(DMSO-d₆) δ: 9.75 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.56 (d, J = 9.3Hz, 1H), 7.43- 7.40 (m, 2H), 7.07 (s, 1H), 7.03 (d, J = 7.7 Hz, 1H),6.58 (s, 1H), 5.27 (s, 2H), 4.23 (q, J = 7.3 Hz, 2H), 4.01 (s, 3H), 2.42(s, 3H), 2.28 (s, 3H), 1.43 (t, J = 7.3 Hz, 3H) 403 (M⁺),  359, 213(base) Example 12-20 Example 11-13

(DMSO-d₆) δ: 9.66 (br s, 1H), 8.27 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H),7.85 (s, 1H), 7.53 (d, J = 9.2 Hz, 1H), 7.22 (dd, J = 1.2, 9.2 Hz, 1H),7.17 (d, J = 1.9 Hz, 1H), 7.03 (dd, J = 1.9, 8.1 Hz, 1H), 6.83 (s, 1H),5.25 (s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 1.49(t, J = 7.3 Hz, 3H) 439 (M⁺),  395, 159 (base) Example 12-27 —

(DMSO-d₆) δ: 9.65 (br s, 1H), 8.10 (s, 1H), 7.82 (s, 1H), 7.49-7.44 (m,2H), 7.33 (dd, J = 1.9, 8.9 Hz, 1H), 7.24 (dd, J = 1.9, 7.3 Hz, 1H),7.16 (d, J = 8.5 Hz, 1H), 7.05 (dt, J = 0.8, 7.3 Hz, 1H), 6.28 (s, 1H),5.10 (s, 2H), 3.86 (q, J = 7.3 Hz, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 1.25(t, J = 7.3 Hz, 3H) 405 (M⁺),  361, 215 (base)

TABLE 142 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-32 —

(DMSO-d₆) δ: 9.63 (s, 1H), 8.10 (s, 1H), 7.81 (ds, 1H), 7.45 (d, J = 8.9Hz, 1H), 7.34-7.28 (m, 2H), 7.09 (dd, J = 2.3, 11.6 Hz, 1H), 6.88 (dt, J= 2.3, 8.5 Hz, 1H), 6.31 (s, 1H), 5.08 (s, 2 H), 3.82 (s, 3H), 3.80 (s,3H), 3.60 (s, 3H) 409 (M⁺), 365, 236, 219 (base), 173 Example 12-26 —

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.45 (d, J =8.5 Hz, 1H), 7.33 (dd, J = 1.9, 8.9 Hz, 1H), 7.30-7.23 (m, 2H), 7.09(dd, J = 2.3, 11.6 Hz, 1H), 6.88 (dd, J = 2.3, 8.5 Hz, 1H), 6.28 (s,1H), 5.09 (s, 2H), 4.03 (q, J = 6.9 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H),1.25 (t, J = 6.9 Hz, 3H) 423 (M⁺), 379, 173 (base) Example 12-30 —

(DMSO-d₆) δ: 9.63 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.44-7.45 (m,1H), 7.33-7.24 (m, 3H), 7.18-7.03 (m, 1H), 6.33 (s, 1H), 5.09 (s, 2H),3.83 (s, 3H), 3.79 (s, 3H), 3.60 (s, 3H) 425 (M⁺), 381, 252, 173 (base)Example 12-28 —

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.45 (d, J = 8.9 Hz, 1H), 8.10 (s, 1H),7.81 (s, 1H), 7.33 (dd, J = 1.9, 8.9 Hz, 1H), 7.26 (d, J = 6.2 Hz, 1H),7.25 (s, 1H), 7.11 (dd, J = 1.9, 8.1 Hz, 1H), 6.30 (s, 1H), 5.09 (s,2H), 3.88- 3.82 (m, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 1.25 (t, J = 7.3Hz) 439 (M⁺), 395, 266, 249, 173 (base)

TABLE 143 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-18 —

(DMSO-d₆) δ: 9.62 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.45 (d, J = 8.9Hz, 1H), 7.34 (d, J = 1.5 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 6.99 (s,1H), 6.87 (d, J = 7.7 Hz, 1H), 6.27 (s, 1H), 5.08 (s, 2H), 3.80 (s, 3H),3.79 (s, 3H), 3.59 (s, 3H), 2.38 (s, 3H) 405 (M⁺), 316, 232, 215 (base),173 Example 12-29 —

(DMSO-d₆) δ: 9.65 (brs, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.45 (d, J =8.9 Hz, 1H), 7.33 (dd, J = 1.9 Hz, 8.9 Hz, 1H), 7.10 (d, J = 7.7 Hz,1H), 6.99 (s, 1H), 6.87-6.85 (m, 1H), 6.23 (s, 1H), 5.09 (s, 2H), 4.03(q, J = 7.3 Hz, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.38 (s, 3H), 1.24 (t,J = 7.3 Hz, 3H) 419 (M⁺), 375, 246, 173 (base) Example 12-31 —

(DMSO-d₆) δ: 9.64 (s, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.45 (d, J = 8.5Hz, 1H), 7.34 (d, J = 8.9 Hz, 1H), 7.18 (s, 1H), 7.15-7.09 (m, 2H), 6.31(s, 1H), 5.10 (s, 2H), 3.80 (s, 3H), 3.57 (s, 3H), 2.33 (s, 3H), 2.11(s, 3H) 389 (M⁺), 345, 216, 199 (base) Example 12-27 Example 11-5

(DMSO-d₆) δ: 9.66 (brs, 1H), 7.78 (s, 1H), 7.47 (ddd, J = 1.5, 7.7, 8.5Hz, 1H), 7.41 (d, J = 8.9, 1H), 7.29 (dd, J = 1.9, 8.5 Hz, 1H), 7.24(dd, J = 1.9, 7.7 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.05 (dt, J = 1.2,7.7 Hz, 1H), 6.28 (s, 1H), 5.10 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H),3.86 (q, J = 7.3 Hz, 2H), 3.78 (s, 3H), 1.25 (t, 7.3 Hz, 3H) 447 (M⁺),403, 215 (base) Example 12-26 Example 11-5

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H),7.30- 7.26 (m, 2H), 7.09 (dd, J = 2.3, 11.2 Hz, 1H), 6.88 (dt, J = 2.3,8.5 Hz, 1H), 6.27 (s, 1H), 5.09 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H),3.84 (q, J = 7.3 Hz, 2H), 3.80 (s, 3H), 1.25 (t, J = 7.3 Hz, 3H) 465(M⁺), 421, 215 (base)

TABLE 144 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-30 Example 11-5

(DMSO-d₆) δ: 9.64 (s, 1H), 7.77 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.29-7.25 (m, 3H), 7.13- 7.05 (m, 1H), 6.33 (s, 1H), 5.08 (s, 2H), 4.92 (s,2H), 4.14 (s, 4H), 3.83 (s, 3H), 3.60 (s, 3H) 467 (M⁺), 423, 252, 215(base) Example 12-28 Example 11-5

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.77 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H),7.30-7.25 (m, 3H), 7.11 (dd, J = 1.9, 8.1 Hz, 1H), 6.29 (s, 1H), 5.09(s, 2H), 4.91 (s, 2H), 4.15 (s, 4H), 3.87-3.84 (m, 2H), 3.81 (s, 3H),1.25 (t, J = 7.3 Hz, 3H) 437 (M⁺ − 44), 266, 215 (base) Example 12-18Example 11-5

(DMSO-d₆) δ: 9.63 (s, 1H), 7.77 (s, 1H), 7.71 (s, 1H), 7.41 (d, J = 8.9Hz, 1H), 7.29 (dd, J = 1.5, 8.9 Hz, 1H), 6.99 (s, 1H), 6.86 (d, J = 7.7Hz, 1H), 6.27 (s, 1H), 5.07 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H), 3.79(s, 3H), 3.59 (s, 3H), 2.38 (s, 3H) 447 (M⁺), 403, 232, 215 (base)Example 12-29 Example 11-5

(DMSO-d₆) δ: 9.65 (brs, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H),7.29 (dd, J = 1.9, 8.9 Hz, 1H), 7.10 (d, J = 7.3 Hz, 1H), 6.99 (s, 1H),6.86 (d, J = 6.9 Hz, 1H), 6.23 (s, 1H), 5.08 (s, 2H), 4.92 (s, 2H), 4.14(s, 4H), 3.84 (q, J = 7.3 Hz, 2H), 3.77 (s, 3H), 2.37 (s, 3H), 1.24 (t,7.3 Hz, 3H) 461 (M⁺), 417, 246, 215 (base) Example 12-31 Example 11-5

(DMSO-d₆) δ: 9.65 (s, 1H), 7.78 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.29(dd, J = 1.2, 8.1 Hz, 1H), 7.18 (s, 1H), 7.14-7.11 (m, 2H), 6.31 (s,1H), 5.10 (s, 2H), 4.92 (s, 2H), 4.14 (s, 4H), 3.57 (s, 3H), 2.33 (s,3H), 2.11 (s, 3H) 431 (M⁺), 387, 215 (base), 199

TABLE 145 Hydroxy Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 12-34 —

(DMSO-d₆) δ: 9.70 (brs, 1H), 8.10 (s, 1H), 7.81 (s, 1H), 7.77 (dd, J =6.1, 8.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 1.2, 8.5 Hz,1H), 7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.15 (dt, J = 3.1, 8.5 Hz, 1H),5.39 (s, 2H), 3.80 (s, 3H), 2.85 (q, J = 7.7 Hz, 2H), 2.56 (s, 3H), 1.28(t, J = 7.3 Hz, 3H) 424 (M⁺), 409, 380 Example 12-34 Example 11-5

(DMSO-d₆) δ: 9.71 (brs, 1H), 7.79-7.75 (m, 2H), 7.42 (d, J = 8.5 Hz,1H), 7.29 (d, J = 8.9 Hz, 1H), 7.25 (dd, J = 2.7, 10.0 Hz, 1H), 7.15(dt, J = 2.7, 8.5 Hz, 1H), 5.39 (s, 2H), 4.92 (s, 2H), 4.41 (brs, 4H),2.85 (q, J = 7.3 Hz, 2H), 2.55 (s, 3H), 1.28 (t, J = 7.3 Hz, 3H) 466(M⁺), 422, 234 (base)

In the formulae, R represents an alkyl group, and R′ represents an arylor heterocyclic group which may have a substituent (such as a halogenatom, an alkoxy group, or an alkylthio group).

Example 14-1 Step 14-1-1 4-Methoxybenzoic acid N-methyl hydrazide

Methylhydrazine (2.76 g) was dissolved in dichloromethane (60 ml), and asolution of 4-methoxybenzoyl chloride (5.12 g) in dichloromethane (10ml) was added thereto under an ice cooling and stirring. The mixture wasfurther stirred at a room temperature for 1.5 hours, and then thereaction solution washed with water and a saturated saline solution inorder. The washed product was dried over anhydrous sodium sulfate,concentrated under a reduced pressure, and dried to give the titlecompound (4.81 g, 89%).

¹H-NMR (CDCl₃) δ: 7.54 (d, J=8.9 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 3.83(s, 3H), 3.24 (s, 3H)

Mass, m/z: 180 (M⁺), 135 (base)

Step 14-1-2 N-(4-Methoxybenzyl)-N-methylhydrazine

Tetrahydrofuran (40 ml) was added to lithium aluminumhydride (1.94 g),the mixture was heated and stirred gently under an argon atmosphere, anda solution (10 ml) of 4-methoxybenzoic acid N-methyl hydrazide (4.78 g)prepared in the Step 14-1-1 in THF was added thereto. The resultingmixture was further stirred for 15 hours under heat reflux. The mixturewas allowed to cool to a room temperature, and then water (2 ml) and a1-N sodium hydroxide aqueous solution (7.5 ml) were added dropwise tothe mixture. The reaction solution was filtered through a celite, andthe filtrate was concentrated under a reduced pressure. The concentratewas purified by silica gel column chromatography(dichloromethane:methanol=50:1) to give the title compound (2.27 g,45%).

¹H-NMR (CDCl₃) δ: 7.70 (d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 3.80(s, 3H), 3.56 (s, 2H), 2.49 (s, 3H)

Mass, m/z: 166 (M⁺), 121 (base)

Example 14-2 N-Ethyl-N-(4-methoxybenzyl)hydrazine

The title compound was obtained according to the same procedure as inExample 14-1 except that ethylhydrazine was used instead ofmethylhydrazine.

¹H-NMR (CDCl₃) δ: 7.24 (d, J=8.1 Hz, 2H), 6.87 (d, J=8.9 Hz, 2H), 3.80(s, 3H), 3.61 (s, 2H), 2.59 (q, J=7.3 Hz, 2H), 1.15 (t, J=7.3 Hz, 3H)

Mass, m/z: 180 (M⁺), 121 (base)

Examples 14-3 to 14-7

The objective compounds were obtained according to the same procedure asin Example 14-1 except that any one of acid chloride components shown inthe following table was used instead of 4-methoxybenzoyl chloride.

TABLE 146 Acid chloride Mass, component Example ¹H-NMR m/z3,4-Dimethoxybenzoyl chloride

(CDCl₃) δ: 6.90 (brs, 1H), 6.82 (s, 1H), 6.82 (s, 1H), 3.89 (s, 3H),3.87 (s, 3H), 3.56 (s, 2H), 2.50 (s, 3H) 196 (M⁺), 151 (base)2,3-Dihydro-1- benzofuran-5- carbonyl chlorlide

(CDCl₃) δ: 7.17 (brs, 1H), 7.02 (dd, J = 0.8 Hz, 8.1 Hz, 1H), 6.73 (d, J= 8.1 Hz, 1H), 4.56 (t, J = 8.9 Hz, 2H), 3.53 (s, 2H), 3.19 (t, J = 8.9Hz, 2H), 2.49 (s, 3H) 178 (M⁺), 133 (base) 4-Ethoxybenzoyl chloride

(CDCl₃) δ: 7.22 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 4.02 (q,J = 7.0 Hz, 2H), 3.55 (s, 2H), H), 2.49 (s, 3H), 1.40 (t, J = 7.0 Hz,3H) 180 (M⁺), 107 (base) 3-Fluoro-4- methoxybenzoyl chloride

(CDCl₃) δ: 7.08 (dd, J = 1.9, 12.0 Hz, 1H), 7.01 (brd, J = 8.1 Hz, 1H),6.91 (dd, J = 8.1 Hz, 8.5 Hz, 1H), 3.88 (s, 3H), 3.54 (s, 2H), 2.49 (s,3H) 184 (M⁺), 139 (base) 4-Methylthiobenzoyl chloride

(CDCl₃) δ: 7.24 (brs, 4H), 3.58 (s, 2H), 2.50 (s, 3H), 2.48 (s, 3H) 182(M⁺), 137 (base)

In the formulae, R represents an alkyl group, and R′ represents an arylgroup which may have a substituent (such as an alkyl group, a hydroxylgroup, or an alkoxy group).

Example 15-1 Step 15-1-12-{[1-(4-Methoxy-3-methylphenyl)-methylidene]amino}isoindole-1,3-dione

N-aminophthalimide (1.62 g) and 4-methoxy-3-methylbenzaldehyde (1.50 g)were added to ethanol (20 ml), the mixture was stirred under heat refluxovernight. The mixture was allowed to cool to a room temperature, andthen the precipitate was separated by filtration, washed with ethanol,and dried under a reduced pressure to give the title compound (2.50 g,84%).

¹H-NMR (CDCl₃) δ: 9.19 (s, 1H), 7.90 (dd, J=3.1 Hz, 5.4 Hz, 2H), 7.77(brs, 1H), 7.76 (dd, J=3.1 Hz, 5.4 Hz, 2H), 7.64 (dd, J=2.3 Hz, 8.5 Hz,1H), 6.87 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 2.26 (s, 3H)

Mass, m/z: 294 (M⁺), 147 (base)

Step 15-1-2 2-(4-Methoxy-3-methylbenzylamino)isoindole-1,3-dione

Acetic acid (40 ml) and pyridine-borane (4.3 ml) were added to2-{[1-(4-methoxy-3-methylphenyl)-methylidene]amino}isoindole-1,3-dione(2.50 g) prepared in the Step 15-1-1, and the mixture was stirred undera room temperature for 0.5 hours. The mixture was concentrated under areduced pressure, and under an ice cooling 10% hydrochloric acid (10 ml)was added to the resulting residue. Sodium hydroxide (1.1 g) was addedthereto, and the resulting mixture was subjected to extraction withethyl acetate. The organic layer was washed with a saturated salinesolution, and then dried over sodium sulfate and concentrated under areduced pressure. To the resulting residue, ethanol (10 ml) was added,and the mixture was stirred at a room temperature. The precipitate wasseparated by filtration, washed with ethanol, and concentrated under areduced pressure to give the title compound (1.71 g, 68%).

¹H-NMR (CDCl₃) δ: 7.83 (dd, J=3.1 Hz, 5.4 Hz, 2H), 7.72 (dd, J=3.1 Hz,5.4 Hz, 2H), 7.23 to 7.20 (m, 2H), 6.76 (d, J=8.9 Hz, 1H), 4.68 (brd,J=5.0 Hz, 1H), 4.10 (d, J=5.0 Hz, 2H), 3.80 (s, 3H), 2.19 (s, 3H)

Mass, m/z: 296 (M⁺), 135 (base)

Step 15-1-3 2-[(4-Methoxy-3-methylbenzyl)methylamino]isoindole-1,3-dione

N,N-dimethylformamide (20 ml), methyl iodide (0.7 ml) and potassiumcarbonate (3.12 g) were added to2-(4-methoxy-3-methylbenzylamino)isoindole-1,3-dione (1.67 g) preparedin the Step 15-1-2, and the mixture was stirred overnight. Methyl iodide(0.35 ml) was added thereto, and the resulting mixture was stirred foranother 5 hours. Thereafter, an ethyl acetate-toluene (3:1) solution wasadded thereto. The resulting mixture was washed with water and asaturated saline solution in order, and then dried over sodium sulfateand concentrated under a reduced pressure. To the resulting residue,diethyl ether was added, and the mixture was stirred at a roomtemperature. The precipitate was separated by filtration, washed withdiethyl ether, and dried under a reduced pressure to give the titlecompound (1.15 g, 65%).

¹H-NMR (CDCl₃) δ: 7.74 (dd, J=3.1 Hz, 5.4 Hz, 2H), 7.66 (dd, J=3.1 Hz,5.4 Hz, 2H), 7.16 to 7.12 (m, 2H), 6.66 (d, J=8.8 Hz, 1H), 4.31 (s, 2H),3.74 (s, 3H), 3.06 (s, 3H), 2.11 (s, 3H)

Mass, m/z: 310 (M⁺), 135 (base)

Step 15-1-4 N-(4-Methoxy-3-methylbenzyl)-N-methylhydrazine

Tetrahydrofuran (30 ml) and methylhydrazine (138 mg) were added to2-[(4-methoxy-3-methylbenzyl)methylamino]isoindole-1,3-dione (621 mg)prepared in the Step 15-1-3, and the mixture was stirred at a roomtemperature for one hour. Another methylhydrazine (138 mg) was addedthereto, the resulting mixture was stirred for 12 hours. The solvent wasdistilled off under a reduced pressure. Dichloromethane was added to theresidue, and the insoluble matter was removed by filtration. Thefiltrate was concentrated under a reduced pressure and then purified bysilica gel column chromatography (dichloromethane:methanol=20:1) to givethe title compound (115 mg, 31%).

¹H-NMR (CDCl₃) δ: 7.12 to 7.08 (m, 2H), 6.78 (d, J=8.5 Hz, 1H), 3.82 (s,3H), 3.57 (s, 2H), 3.27 (brs, 2H), 2.52 (s, 3H), 2.20 (s, 3H)

Mass, m/z: 180 (M⁺), 135 (base)

Example 15-2 2-Methoxy-5-(N-methylhydrazinomethyl)phenol

The title compound was obtained according to the same procedure as inExample 15-1 except that 3-hydroxy-4-methoxybenzaldehyde was usedinstead of 4-methoxy-3-methylbenzaldehyde.

¹H-NMR (CDCl₃) δ: 6.91 (d, J=1.5 Hz, 1H), 6.81 to 6.79 (m, 2H), 3.88 (s,3H), 3.53 (s, 2H), 2.49 (s, 3H)

Mass, m/z: 182 (M⁺), 137 (base)

In the formulae, R and R′″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, or an alkoxy group), and R′ and R″ are the same ordifferent and each represent a hydrogen atom or an alkyl group.

Example 16-1 2-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid N′-(4-methoxybenzyl)-N′-methyl hydrazide

To N,N-dimethylformamide (12 ml),2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (1.02 g)prepared in Example 7-1, N-(4-methoxybenzyl)-N-methylhydrazine (718 mg)prepared in Example 14-1, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (828 mg), 1-hydroxy-1H-benzotriazole monohydrate (662 mg)and N,N-diisopropylethylamine (558 mg), and the mixture was stirred at aroom temperature for 22 hours. An ethyl acetate-toluene (3:1) solutionwas added thereto. The resulting mixture was washed with water, a 5%potassium bisulfate aqueous solution, a saturated sodium bicarbonatesolution and a saturated saline solution in order, and then dried oversodium sulfate and concentrated under a reduced pressure. Theconcentrate was purified by silica gel column chromatography(chloroform:methanol=100:1) to give the title compound (1.05 g, 67%).

¹H-NMR (DMSO-d₆) δ: 9.17, 8.81 (two s, 1H), 8.29, 8.25 (two d, J=8.1 Hz,1H), 7.37 (brs, 1H), 7.29 (d, J=8.5 Hz, 2H), 7.18 (dd, J=2.0 Hz, 8.5 Hz,1H), 6.86 (d, J=8.5 Hz, 2H), 4.07 (s, 3H), 3.91 to 3.79 (m, 2H), 3.72(s, 3H), 2.63, 2.60 (two s, 3H), 2.53, 2.41 (two s, 3H)

Mass, m/z: 431 (M⁺), 121 (base)

Examples 16-2 to 16-25

The objective compounds were obtained according to the same procedure asin Example 16-1 except that carboxylic acids or hydrazine compoundsshown in the following tables were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid orN-(4-methoxybenzyl)-N-methylhydrazine.

TABLE 147 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/z2-(4- Chloro phenyl)-4- methyl- thiazole-5- carboxylic acid —

(DMSO-d₆) δ: 9.24, 8.83 (two s, 1H), 7.96 (d, J = 8.5 Hz, 2H), 7.59 (d,J = 8.5 Hz, 2H), 7.28, 7.24 (two d, J = 8.1 Hz, 2H), 6.88, 6.82 (two d,J = 8.1 Hz, 2H), 3.91- 3.71 (m, 2H), 3.70 (s, 3H), 2.64, 2.60 (two s,3H), 2.56, 2.40 (two s, 3H) 401 (M⁺), 121 base) Example 7-9 —

(DMSO-d₆) δ: 9.22, 8.82 (two s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.43-7.32(m, 3H), 7.29, 7.23 (two d, J = 8.1 Hz, 2H), 6.88, 6.81 (two d, J = 8.5Hz, 2H), 3.92-3.72 (m, 2H), 3.71 (s, 3H), 2.64, 2.57 (two s, 6H), 2.54,2.42 (two s, 3H) 381 (M⁺), 121 base) Example 7-8 —

(DMSO-d₆) δ: 9.14, 8.77 (two s, 1H), 8.30, 8.26 (two d, J = 7.7 Hz, 1H),7.49 (ddd, J = 1.6 Hz, 7.3 Hz, 8.5 Hz, 1H), 7.30 (d, J = 8.9 Hz, 2H),7.26 (brd, J = 8.5 Hz, 1H), 7.11 (dd, J = 7.3 Hz, 7.7 Hz, 1H), 6.86 (d,J = 7.7 Hz, 2H), 4.04 (s, 3H), 3.92-3.76 (m, 2H), 3.72 (s, 3H), 2.64,2.60 (two s, 3H), 2.53, 2.42 (two s, 3H) 397 (M⁺), 121 base) 2-(2,3-Dimethyl phenyl)-4- methyl- thiazole-5- carboxylic acid —

(DMSO-d₆) δ: 9.21, 8.79 (two s, 1H), 7.39 (d, J = 7.3 Hz, 1H), 7.32 (d,J = 7.3 Hz, 1H), 7.25-7.19 (m, 3H), 6.81 (d, J = 8.5 Hz, 2H), 3.92-3.72(m, 2H), 3.71 (s, 3H), 2.64, 2.57 (two s, 3H), 2.56, 2.41 (two s, 3H),2.36 (s, 3H), 2.34 (s, 3H) 395 (M⁺), 121 base)

TABLE 148 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/zExample 7-7 —

(DMSO-d₆) δ: 9.24, 8.85 (two s, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.50 (d,J = 2.3 Hz, 1H), 7.42 (brd, J = 8.1 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H),6.81 (d, J = 8.5 Hz, 2H), 3.92-3.72 (m, 2H), 3.71 (s, 3H), 2.64, 2.57(two s, 6H), 2.56, 2.42 (two s, 3H) 415 (M⁺), 121 (base) Example 7-38 —

(DMSO-d₆) δ: 9.26, 8.89 (two s, 1H), 8.32-8.23 (m, 1H), 7.53 (ddd, J =2.3 Hz, 9.3 Hz, 11.6 Hz, 1H), 7.28 (ddd, J = 2.3 Hz, 8.1 Hz, 8.5 Hz,1H), 7.24 (d, J = 8.5 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 3.92-3.76 (m,2H), 3.71 (s, 3H), 2.64, 2.60 (two s, 3H), 2.56, 2.45 (two s, 3H) 403(M⁺), 121 (base) Example 7-13 —

(DMSO-d₆) δ: 9.14, 8.77 (two s, 1H), 8.35-8.26 (m, 1H), 7.29 (d, J = 8.9Hz, 2H), 7.19 (dd, J = 2.3 Hz, 11.2 Hz, 1H), 6.95 (ddd, J = 2.3 Hz, 8.5Hz, 8.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 2H), 4.05 (s, 3H), 3.92-3.78 (m,2H), 3.72 (s, 3H), 2.63, 2.59 (two s, 3H), 2.52, 2.41 (two s, 3H) 415(M⁺), 121 (base) 2-(2- Chloro-4- methoxy- phenyl)- 4-methyl thiazole-5-carboxylic acid —

(DMSO-d₆) δ: 9.21, 8.86 (two s, 1H), 8.16 (d, J = 8.9 Hz, 1H), 7.27 (d,J = 8.5 Hz, 2H), 7.23 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 2.3 Hz, 8.9 Hz,1H), 6.81 (d, J = 8.5 Hz, 2H), 3.91- 3.78 (m, 2H), 3.87 (s, 3H), 3.71(s, 3H), 2.64, 2.60 (two s, 3H), 2.53, 2.42 (two s, 3H) 431 (M⁺), 121(base)

TABLE 149 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/z2-(2,4- Dichloro phenyl)-4- methyl- thiazole- 5-carboxylic acid —

(CDCl₃) δ: 8.26 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.36 (dd, J = 1.9 Hz,8.5 Hz, 1H), 7.25 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 6.17(s, 1H), 4.07-3.74 (m, 2H), 3.80 (s, 3H), 2.79 (s, 3H), 2.57 (s, 3H) 435(M⁺), 121 (base) Example 7-16 —

(CDCl₃) δ: 7.65 (d, J = 7.7 Hz, 1H), 7.27- 7.18 (m, 2H), 7.12 (s, 1H),7.08 (d, J = 7.7 Hz, 1H), 6.85 (d, J = 7.7 Hz, 2H), 6.11 (s, 1H), 4.08-3.74 (m, 2H), 3.79 (s, 3H), 2.78 (s, 3H), 2.56 (s, 6H), 2.36 (s, 3H) 395(M⁺), 121 (base) Example 7-8 Example 14-2

(CDCl₃) δ: 8.46-8.35 (m, 1H), 7.44-7.39 (m, 1H), 7.28 (d, J = 8.8 Hz,2H), 7.12-7.01 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.43, 5.97 (two s,1H), 4.04 (s, 3H), 4.03  

  3.81 (m, 2H), 3.79 (s, 3H), 3.02- 2.92, 2.60-2.53 (two m, 2H), 2.79,2.62 (two s, 3H), 1.21- 1.14 (m, 3H) 411 (M⁺), 121 (base) — Example 14-2

(CDCl₃) δ: 8.39, 8.31 (two d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.9 Hz, 2H),7.10-7.01 (m, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.41, 5.97 (two s, 1H),4.14-3.81 (m, 2H), 4.04 (s, 3H), 3.79 (s, 3H), 3.01-2.91, 2.60-2.54 (twom, 2H), 2.78, 2.59 (two s, 3H), 1.20-1.14 (m, 3H) 445 (M⁺), 121 (base)

TABLE 150 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/z2-(2,3- Dimethyl phenyl)-4- methyl- thiazole- 5-carboxylic acid Example14-2

(DMSO-d₆) δ: 9.01, 8.59 (two s, 1H), 7.37 (d, J = 7.4 Hz, 1H),7.33-7.28, 7.25-7.19 (m, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.87, 6.78 (twod, J = 8.5 Hz, 2H), 3.94-3.64 (m, 2H), 3.73, 3.70 (two s, 3H), 2.95-2.86, 2.74-2.67 (two m, 2H), 2.53, 2.40 (two s, 3H), 2.35, 2.34 (two s,6H), 1.07 (t, J = 7.0 Hz, 3H) 409 (M⁺), 121 (base) Example 7-7 Example14-2

(DMSO-d₆) δ: 9.04, 8.66 (two s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.50 (d,J = 1.9 Hz, 1H), 7.42 (dd, J = 1.9 Hz, 8.1 Hz, 1H), 7.30, 7.23 (two d, J= 8.5 Hz, 2H), 6.87, 6.79 (two d, J = 8.5 Hz, 2H), 3.93-3.67 (m, 2H),3.73, 3.69 (two s, 3H), 2.94- 2.86, 2.74-2.68 (two m, 2H), 2.55, 2.40(two s, 6H), 1.06 (t, J = 7.3 Hz, 3H) 429 (M⁺), 121 (base) — Example14-3

(DMSO-d₆) δ: 9.16, 8.79 (two s, 1H), 8.29, 8.25 (two d, J = 8.5 Hz, 1H),7.37 (s, 1H), 7.18 (dd, J = 1.9 Hz, 8.5 Hz, 1H), 7.04, 6.87 (two brs,1H), 6.85 (s, 2H), 4.06, 4.03 (two s, 3H), 3.93-3.73 (m, 2H), 3.71, 3.51(two s, 6H), 2.67, 2.60 (two s, 3H), 2.55, 2.41 (two s, 3H) 461 (M⁺),151 (base) Example 7-7 Example 14-3

(DMSO-d₆) δ: 9.21, 8.85 (two s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.50 (d,J = 1.9 Hz, 1H), 7.41 (dd, J = 2.0 Hz, 8.5 Hz, 1H), 7.06-7.02, 6.88-6.78 (m, 3H), 3.93-3.71 (m, 2H), 3.70, 3.52 (two s, 6H), 2.67, 2.60 (twos, 3H), 2.56, 2.41 (two s, 3H), 2.54 (s, 3H) 445 (M⁺), 151 (base)

TABLE 151 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/z —Example 14-4

(DMSO-d₆) δ: 9.18, 8.76 (two s, 1H), 8.29, 8.26 (two d, J = 8.5 Hz, 1H),7.37 (s, 1H), 7.24, 7.14 (two s, 1H), 7.18 (dd, J = 1.9 Hz, 8.5 Hz ,1H), 7.07 (brd, J = 7.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 4.52-4.45 (m,2H), 4.07 (s, 3H), 3.87, 3.77 (two s, 2H), 3.17-3.02 (m, 2H), 2.62, 2.57(two s, 3H), 2.54, 2.44 (two s, 3H) 443 (M⁺), 133 (base) — Example 14-5

(DMSO-d₆) δ: 9.16, 8.80 (two s, 1H), 8.29, 8.25 (two d, J = 8.5 Hz, 1H),7.37 (brs, 1H), 7.27 (d, J = 8.5 Hz, 2H), 7.18 (dd, J = 1.9 Hz, 8.5 Hz,1H), 6.84 (d, J = 8.5 Hz, 2H), 4.07 (s, 3H), 3.99 (q, J = 6.9 Hz, 2H),3.90-3.77 (m, 2H), 2.63, 2.60 (two s, 3H), 2.52, 2.41 (two s, 3H), 1.30(t, J = 6.9 Hz, 3H) 445 (M⁺), 135 (base) — Example 14-6

(DMSO-d₆) δ: 9.21, 8.83 (two s, 1H), 8.29, 8.25 (two d, J = 8.1 Hz, 1H),7.38 (d, J = 1.9 Hz, 1H), 7.30- 7.15 (m, 2H), 7.12-7.05 (m, 2H), 4.07(s, 3H), 3.92, 3.72 (two s, 3H), 3.80 (s, 3H), 2.66, 2.59 (two s, 3H),2.56, 2.42 (two s, 3H) 449 (M⁺), 266 (base) 2-(2,4- Difluoro phenyl)-4-methyl- thiazole- 5-carboxylic acid Example 14-6

(DMSO-d₆) δ: 9.31, 8.91 (two s, 1H), 8.31- 8.24 (m, 1H), 7.53 (ddd, J =2.3 Hz, 9.2 Hz, 11.6 Hz, 1H), 7.29 (ddd, J = 2.3 Hz, 8.5 Hz, 8.8 Hz,1H), 7.24-7.02 (m, 3H), 3.93- 3.71 (m, 2H), 3.79 (s, 3H), 2.67, 2.59(two s, 3H), 2.58, 2.45 (two s, 3H) 421 (M⁺), 139 (base)

TABLE 152 Carboxylic Hydrazine Mass, acid compound Example ¹H-NMR m/z —Example 14-7

(DMSO-d₆) δ: 9.20, 8.84 (two s, 1H), 8.32- 8.23 (m, 1H), 7.37 (d, J =1.9 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 7.24-7.16 (m, 3H), 4.07 (s, 3H),3.94, 3.84 (two s, 2H), 2.66, 2.59 (two s, 3H), 2.55, 2.41 (two s, 3H),2.44 (s, 3H) 447 (M⁺), 137 (base) — Example 15-1

(DMSO-d₆) δ: 9.17, 8.77 (two s, 1H), 8.29, 8.25 (two d, J = 8.5, 1H),7.37 (s, 1H), 7.18 (dd, J = 1.6 Hz, 8.5 Hz, 1H), 7.15, 7.05 (two brs,1H), 7.14 (d, J = 7.0 Hz, 1H), 6.83 (d, J = 8.5 Hz, 1H), 4.06 (s, 3H),3.87, 3.76 (two s, 2H), 3.74 (s, 3H), 2.62, 2.56 (two s, 3H), 2.55, 2.43(two s, 3H), 2.14, 2.03 (two s, 3H) 445 (M⁺), 135 (base) — Example 15-2

(DMSO-d₆) δ: 9.15, 8.83 (two s, 1H), 8.80, 8.77 (two s, 1H), 8.30, 8.25(two d, J = 8.5, 1H), 7.37 (brs, 1H), 7.18 (dd, J = 1.9 Hz, 8.5 Hz, 1H),6.86-6.74 (m, 3H), 4.06 (s, 3H), 3.84-3.69 (two s, 2H), 3.74 (s, 3H),2.74, 2.62 (two s, 3H), 2.61, 2.44 (two s, 3H) 447 (M⁺), 137 (base)Example 7-7 Example 15-1

(DMSO-d₆) δ: 9.23, 8.83 (two s, 1H), 8.83, 8.80 (two s, 1H), 7.82, 7.78(two d, J = 8.5, 1H), 7.50 (d, J = 2.3 Hz, 1H), 7.41 (dd, J = 1.6 Hz,8.5 Hz, 1H), 6.84-6.68 (m, 3H), 3.83, 3.71 (two s, 2H), 3.72 (s, 3H),2.74, 2.61 (two s, 3H), 2.56 (s, 3H), 2.54, 2.44 (two s, 3H) 431 (M⁺),137 (base)

In the formulae, R and R′″ are the same or different and each representan aryl or heterocyclic group which may have a substituent (such as ahalogen atom, an alkyl group, a hydroxyl group, or an alkoxy group), andR′ and R″ are the same or different and each represent a hydrogen atomor an alkyl group.

Example 17-1 Step 17-12-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acidN′-(1-methyl-1H-indol-5-ylmethyl)hydrazide

A mixture of 2-(4-chloro-2-methylphenyl)-4-methylthiazole-5-carboxylicacid hydrazide (150 mg) prepared in the same manner as in theafter-mentioned Step 23-1-2,1-methyl-1H-indolecarboaldehyde (85 mg),pyridine borane (0.11 ml), acetic acid (1 ml) and methanol (10 ml) wasstirred under a room temperature for 48 hours. To the reaction solution,10% hydrochloric acid (1 ml) was added, and the resulting mixture wasstirred for one hour. Thereafter, the resulting mixture was neutralizedwith a 1-N sodium hydroxide aqueous solution. The neutralized mixturewas concentrated under a reduced pressure, and then the precipitate wasseparated by filtration, washed with water and ethanol in order anddried under a reduced pressure to give the title compound (140 mg, 61%).

¹H-NMR (DMSO-d₆) δ: 7.78 (d, J=8.5 Hz, 1H), 7.53 (s, 1H), 7.50 (s, 1H),7.42 to 7.34 (m, 2H), 7.30 (d, J=3.1 Hz, 1H), 7.19 (brd, J=8.5 Hz, 1H),6.39 (d, J=2.7 Hz, 1H), 4.04, 3.90 (two d, J=5.8 Hz, 2H), 3.78, 3.76(two s, 3H), 2.64, 2.55 (two s, 6H)

Mass, m/z: 424 (M⁺), 144 (base)

Example 17-2 Step 17-22-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acidN′-methyl-N′-(1-methyl-1H-indol-5-ylmethyl)hydrazide

A mixture of 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid N′-(1-methyl-1H-indol-5-ylmethyl)hydrazide (100 mg) prepared in theStep 17-1, a 37% formaldehyde solution (23 mg), pyridine borane (0.07ml), acetic acid (2 ml) and methanol (4 ml) was stirred at a roomtemperature for 41 hours. To the reaction solution, 10% hydrochloricacid (0.5 ml) was added, and the resulting mixture was stirred for 20minutes. Thereafter, the resulting mixture was neutralized with a 1-Nsodium hydroxide aqueous solution. The neutralized mixture wasconcentrated under a reduced pressure. Then, water was added thereto,and the mixture was subjected to extraction twice with ethyl acetate.The organic layer was washed with a saturated sodium bicarbonatesolution and a saturated saline solution in order, dried over sodiumsulfate, and concentrated under a reduced pressure. The concentrate waspurified by a first thin-layer chromatography (chloroform:methanol=20:1)and then a second thin-layer chromatography (hexane:ethyl acetate=1:1)to give the title compound (22 mg, 21%).

¹H-NMR (DMSO-d₆) δ: 9.21, 8.89 (two s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.50(brs, 2H), 7.42 (dd, J=1.6 Hz, 8.5 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 7.28(d, J=3.1 Hz, 1H), 7.15 (brd, J=8.5 Hz, 1H), 6.35 (d, J=2.7 Hz, 1H),4.03, 3.92 (two s, 2H), 3.75 (s, 3H), 2.64, 2.57 (two s, 3H), 2.56, 2.42(two s, 3H), 2.53 (s, 3H)

Mass, m/z: 438 (M⁺), 144 (base)

Example 17-3 2-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid N′-(4-hydroxy-3,5-dimethylbenzyl)hydrazide

The title compound was obtained according to the same procedure as inExample 17-1 except that 4-hydroxy-3,5-dimethylbenzaldehyde was usedinstead of 1-methyl-1H-indolecarboaldehyde.

¹H-NMR (DMSO-d₆) δ: 8.27 (d, J=8.5 Hz, 1H), 8.09 (s, 1H), 7.38 (brs,1H), 7.18 (dd, J=1.6 Hz, 8.5 Hz, 1H), 6.91 (s, 2H), 4.07, 3.97 (two s,3H), 3.79 (d, J=3.8 Hz, 2H), 2.60, 2.54 (two s, 3H), 2.16, 2.12 (two s,6H)

Mass, m/z: 431 (M⁺), 135 (base)

Example 17-4 2-(4-Chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid N′-(4-hydroxy-3,5-dimethylbenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inExample 17-2 except that the compound of Example 17-3 was used insteadof 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acidN′-(1-methyl-1H-indol-5-ylmethyl)hydrazide.

¹H-NMR (DMSO-d₆) δ: 9.14, 8.71 (two s, 1H), 8.29, 8.26 (two d, J=8.5 Hz,1H), 8.09, 8.07 (two s, 1H), 7.38 (d, J=1.5 Hz, 1H), 7.18 (dd, J=1.9 Hz,8.5 Hz, 1H), 6.91, 6.82 (two s, 2H), 4.07, 4.03 (two s, 3H), 3.79, 3.68(two s, 2H), 2.59, 2.55 (two s, 3H), 2.55, 2.46 (two s, 3H), 2.14, 2.05(two s, 6H)

Mass, m/z: 445 (M⁺), 135 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom or analkoxy group), and R′ represents an alkyl group.

Example 18-1 Step 18-1-1 Methyl4-(4-chloro-2-methoxyphenyl)-2,4-dioxobutyrate

To dimethylformamide (13 ml), 1-(4-chloro-2-methoxyphenyl)ethanone (3.13g) and dimethyl oxalate (2.4 g) were added, and 60% sodium hydridesuspension in oil (811 mg) was added thereto at 0° C. The mixture wasstirred at a room temperature for one hour, and then heated to 50° C.and stirred for 19 hours. The mixture was allowed to cool to a roomtemperature, 3-N hydrochloric acid was added to the mixture. Theresulting mixture was subjected to extraction with ethyl acetate. Theorganic layer was washed with water and a saturated saline solution inorder, then dried over anhydrous magnesium sulfate, and concentratedunder a reduced pressure. In the process of the concentration, theprecipitated crystal was separated by filtration to give the titlecompound (2.47 g, 54%).

¹H-NMR (CDCl₃) δ: 15.21 (s, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.04 (dd,J=1.9, 8.2 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H)

Mass, m/z: 270 (M⁺), 211, 169 (base)

Step 18-1-2 Methyl5-(4-chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylate

Methyl 4-(4-chloro-2-methoxyphenyl)-2,4-dioxobutyrate (2.47 g) obtainedin the Step 18-1-1 was dissolved in ethanol (15 ml), and hydrazinemonohydrate (457 mg) was added thereto. The mixture was heated underreflux. After 19 hours, the mixture was allowed to cool to a roomtemperature, the crystal was separated by filtration to give the titlecompound (1.8 g, 74%).

¹H-NMR (DMSO-d₆) δ: 14.14 and 13.64 (two s, 1H), 7.94 and 7.76 (two d,J=8.5 Hz, 1H), 7.26 and 7.23 (two d, J=1.9 Hz, 1H), 7.21 and 7.16 (twod, J=2.3 Hz, 1H), 7.13 and 7.08 (two dd, J=1.9, 8.5 Hz, 1H), 3.95 and3.93 (twos, 3H), 3.87 and 3.83 (two s, 3H)

Mass, m/z: 266 (M⁺) (base), 235, 178, 148, 115

Step 18-1-3 5-(4-Chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylic acid

Ethanol (1 ml) and a 20% sodium hydroxide aqueous solution were mixedwith methyl 5-(4-chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylate (100mg) obtained in the Step 18-1-2, and the mixture was heated underreflux. After one hour, the mixture was allowed to cool to a roomtemperature and acidified with 2-N hydrochloric acid. The precipitatedcrystal was separated by filtration to give the title compound (90 mg,95%).

¹H-NMR (DMSO-d₆) δ: 7.83 (d, J=6.9 Hz, 1H), 7.22 (d, J=1.5 Hz, 1H), 7.10(dd, J=1.9, 7.5 Hz, 1H), 3.93 (s, 3H)

Mass, m/z: 252 (M⁺) (base)

Step 18-1-4 5-(4-Chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylic acidN′-(4-methoxybenzyl)-N′-methyl hydrazide

5-(4-Chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylic acid obtained inthe Step 18-1-3 was used and subjected to the same procedure as inExample 16-1 to give the title compound.

¹H-NMR (DMSO-d₆) δ: 13.58 and 13.27 (two brs, 1H), 9.44 and 8.90 (twobrs, 1H), 7.89 and 7.69 (two d, J=8.5 Hz, 1H), 7.29 (d, J=8.5 Hz, 2H),7.24 (s, 1H), 7.19 and 6.97 (two s, 1H), 7.12 and 7.05 (two d, J=8.5 Hz,1H), 6.85 (d, J=8.5 Hz, 2H), 3.92 (s, 5H), 3.72 (s, 3H), 2.65 and 2.61(two s, 3H)

Mass, m/z: 400 (M⁺), 385, 235, 150, 121 (base)

Example 18-2 5-(4-Chloro-2-methoxyphenyl)-2H-pyrazole-3-carboxylic acidN′-ethyl-N′-(4-methoxybenzyl)hydrazide

The title compound was obtained according to the same procedure as inExample 18-1 except that the compound of Example 14-5 was used insteadof N-(4-methoxybenzyl)-N-methylhydrazine.

¹H-NMR (DMSO-d₆) δ: 13.55 and 13.26 (two brs, 1H), 9.20 and 8.63 (twobrs, 1H), 7.89 and 7.69 (two d, J=8.1 Hz, 1H), 7.30 (d, J=8.5 Hz, 2H),7.24 (s, 1H), 7.19 and 6.96 (two s, 1H), 7.12 and 7.06 (two d, J=8.5 Hz,1H), 6.84 (d, J=8.5 Hz, 2H), 3.94 (s, 2H), 3.92 (s, 3H), 3.71 (s, 3H),2.96-2.81 (m, 2H), 1.02 (brt, J=6.9 Hz, 3H)

Mass, m/z: 414 (M⁺), 399, 235, 164, 121 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom or analkoxy group), and R′ represents an alkyl group.

Example 19-1 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylic acidN′-(4-methoxybenzyl)-N′-methyl hydrazide

Ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate was obtainedaccording to the same procedure as in the after-mentioned Step 27-1-4and then subjected to the same procedure as in the Step 7-1-4 to give3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylic acid. Thecarboxylic acid was used and subjected to the same procedure as inExample 16-1 to give the title compound.

¹H-NMR (CDCl₃) δ: 8.47 (s, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.5Hz, 2H), 7.04 (dd, J=1.9, 8.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.89 (d,J=8.9 Hz, 2H), 6.49 (s, 1H), 3.96 (d, J=13.1 Hz, 1H), 3.91 (s, 3H), 3.88(d, J=12.7 Hz, 1H), 3.80 (s, 3H), 2.63 (s, 3H)

Mass, m/z: 417 (M⁺), 149, 121 (base)

Example 19-2 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylic acidN′-(4-methoxybenzyl)-N′-ethyl hydrazide

The title compound was obtained according to the same procedure as inExample 19-1 except that the compound of Example 14-5 was used insteadof N-(4-methoxybenzyl)-N-methylhydrazine.

¹H-NMR (CDCl₃) δ: 8.48 (s, 1H), 7.97 (d, J=8.5 Hz, 1H), 7.26 (d, J=8.5Hz, 2H), 7.04 (dd, J=1.9, 8.5 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.88 (d,J=8.9 Hz, 2H), 6.32 (s, 1H), 3.99 (d, J=13.1 Hz, 1H), 3.93 (d, J=12.7Hz, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 3.05-2.96 (m, 1H), 2.68-2.59 (m,1H), 1.17 (t, J=7.3 Hz, 3H)

Mass, m/z: 431 (M⁺), 163, 121 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, or an alkoxy group), and R′ represents an alkyl group.

Example 20-1 Step 20-1-1 Ethyl2-[2-(2-methoxyphenyl)-2-oxoethyl-3-oxobutyrate

In tetrahydrofuran (20 ml), 60% sodium hydride suspension in oil (400mg, 10.0 mmol) was suspended, and a solution (5 ml) of ethylacetoacetate (1.30 g, 10.0 mmol) in tetrahydrofuran was added dropwiseto the suspension. After the mixture was stirred for about 30 minutes, asolution (5 ml) of 2-bromo-2′-methoxyacetophenone (2.30 g, 10.0=1) intetrahydrofuran was added dropwise to the mixture. After the mixture wasstirred for about 30 minutes, ethyl acetate was added thereto, and theresulting mixture was washed with water. The organic layer was driedover anhydrous magnesium sulfate and then concentrated. The concentratewas purified by silica gel column chromatography (n-hexane:ethylacetate=5:1) to give the title compound (2.30 g, 83%) as a colorlessoily substance.

¹H-NMR (CDCl₃) δ: 7.75 (dd, J=1.5, 7.7 Hz, 1H), 7.47 (ddd, J=1.5, 7.3,9.2 Hz, 1H), 7.01 to 6.96 (m, 2H), 4.21 (q, J=7.3 Hz, 2H), 4.17 (dd,J=5.8, 8.1 Hz, 1H), 3.70 (dd, J=8.1, 9.3 Hz, 1H), 3.55 (dd, J=5.8, 8.5Hz, 1H), 2.40 (s, 3H), 1.28 (t, J=7.3 Hz, 3H)

Mass, m/z: 278 (m⁺), 135 (base)

Step 20-1-2 Ethyl 5-(2-methoxyphenyl)-2-methylfuran-3-carboxylate

Ethyl 2-[2-(2-methoxyphenyl)-2-oxoethyl-3-oxobutyrate (2.10 g, 7.55mmol) prepared in the Step 20-1-1 was dissolved in ethanol (20 ml), andconcentrated hydrochloric acid (10 ml) was added thereto. The mixturewas heated under reflux for about 16 hours. Water was added to themixture, and the resulting mixture was subjected to extraction withethyl acetate. The organic layer was washed with water, and then driedover anhydrous magnesium sulfate and concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethylacetate=10:1 to 5:1) to give the title compound (1.59 g, 81%) as acolorless oily substance.

¹H-NMR (CDCl₃) δ: 7.80 (dd, J=1.9, 7.7 Hz, 1H), 7.27 to 7.22 (m, 1H),7.13 (s, 1H), 7.03 to 6.95 (m, 2H), 4.32 (q, J=6.9 Hz, 2H), 3.95 (s,3H), 2.64 (s, 3H), 1.37 (t, J=6.9 Hz, 3H)

Mass, m/z: 260 (m⁺), 231 (base)

Step 20-1-3 5-(2-Methoxyphenyl)-2-methylfuran-3-carboxylic acid

Ethyl 5-(2-methoxyphenyl)-2-methylfuran-3-carboxylate (1.00 g, 3.84mmol) prepared in the Step 20-1-2 was dissolved in ethanol (8 ml), and a1 mol/ml sodium hydroxide aqueous solution (8 ml) was added thereto. Themixture was heated under reflux for about 40 minutes. After beingallowed to cool, the mixture was adjusted to weak acidity with 2 mol/mlhydrochloric acid, and the precipitate was filtered. The residue waswashed with water and dried to give the title compound (0.95 g,quantitative) as a white powder.

¹H-NMR (CDCl₃) δ: 7.81 (dd, J=1.5, 7.7 Hz, 1H), 7.28 to 7.24 (m, 1H),7.18 (s, 1H), 7.01 (dt, J=1.2, 7.7 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 3.95(s, 3H), 2.68 (s, 3H)

Mass, m/z: 232 (m⁺, base)

Step 20-1-4 5-(2-Methoxyphenyl)-2-methylfuran-3-carboxylic acidN′-(4-methoxybenzyl)-N′-methyl hydrazide

5-(2-Methoxyphenyl)-2-methylfuran-3-carboxylic acid prepared in the Step20-1-3 and N-(4-methoxybenzyl)-N-methylhydrazine prepared in the Step14-1-2 were used and subjected to the same procedure as in Example 16-1to give the title compound.

¹H-NMR (CDCl₃) δ: 7.79 (d, J=5.8 Hz, 1H), 7.29 to 7.21 (m, 2H), 7.19 (d,J=8.9 Hz, 2H), 7.03 to 6.85 (m, 2H), 6.85 (d, J=8.9 Hz, 2H), 3.94 (s,2H), 3.81 (s, 3H), 3.79 (s, 3H), 2.99, 2.76 (two s, 3H), 2.60 (s, 3H)

Mass, m/z: 380 (m⁺), 121 (base)

Example 20-2 5-(2,4-Dichlorophenyl)-2-methylfuran-3-carboxylic acidN′-(4-methoxybenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inExample 20-1 except that5-(2,4-dichlorophenyl)-2-methylfuran-3-carboxylic acid was used insteadof 5-(2-methoxyphenyl)-2-methylfuran-3-carboxylic acid.

¹H-NMR (CDCl₃) δ: 7.75 (d, J=8.5 Hz, 1H), 7.44 (s, 1H), 7.29 (d, J=8.5Hz, 2H), 7.25 to 7.18 (m, 1H), 6.87 (d, J=8.5 Hz, 2H), 4.03 (s, 2H),3.81 (s, 3H), 3.79 (s, 3H), 2.95, 2.87 (twos, 3H), 2.58 (s, 3H)

Mass, m/z: 418 (m⁺), 121 (base)

Example 20-3 5-(2,4-Dichlorophenyl)-2-methylfuran-3-carboxylic acidN′-(4-methoxy-3,5-dimethylbenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inExample 20-1 except that5-(2,4-dichlorophenyl)-2-methylfuran-3-carboxylic acid andN-(4-methoxy-3,5-dimethylbenzyl)-N-methylhydrazine were used instead of5-(2-methoxyphenyl)-2-methylfuran-3-carboxylic acid andN-(4-methoxybenzyl)-N-methylhydrazine, respectively.

¹H-NMR (CDCl₃) δ: 7.76 (d, J=8.5 Hz, 1H), 7.45 (s, 1H), 7.35 to 7.23 (m,1H), 6.99 (s, 2H), 3.97 (s, 2H), 3.71 (s, 3H), 2.74, 2.59 (two s, 3H),2.50 (s, 3H), 2.69 (s, 6H)

Mass, m/z: 446 (m⁺), 149 (base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom or an alkoxy group); R′ represents an aryl orheterocyclic group which may have a substituent (such as a halogen atom,an alkyl group, a hydroxyl group, an alkoxy group, or a nitro group);and R″ represents a hydrogen atom or an alkyl group.

Example 21-1 Step 21-1-1 5-(2,4-Dichlorophenyl)-2H-pyrazole-3-carboxylicacid hydrazide

In methanol (20 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylicacid (1.00 g) was dissolved, and 6 drops of concentrated sulfuric acidwas added thereto. The mixture was heated under reflux for 19 hours.After the mixture was allowed to cool, hydrazine monohydrate (0.97 g)was added to the mixture, and the resulting mixture was heated underreflux for 16 hours. The mixture was concentrated under a reducedpressure, and water was added thereto. The precipitated crystal wasseparated by filtration, washed with water, and dried to give the titlecompound (912 mg, 87%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 13.88 (brs, 1H), 9.85 and 9.44 (two brs, 1H),7.90-7.60 (m, 2H), 7.52 (s, 1H), 7.38 (s, 1H), 4.50 (brs, 2H)

Mass, m/z: 270 (M⁺), 239 (base)

Step 21-1-2 5-(2,4-Dichlorophenyl)-2H-pyrazole-3-carboxylicacid[1-(2,4-dihydroxyphenyl)methylidene]hydrazide

In ethanol (30 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acidhydrazide (136 mg) prepared in the Step 21-1-1 and2,4-dihydroxybenzaldehyde (69 mg) was heated under reflux for 29 hours.Crystal appeared as the mixture was concentrated under a reducedpressure, the resulting crystal was separated by filtration, washed withethanol, washed with ethyl acetate, and dried to give the title compound(129 mg, 66%).

¹H-NMR (DMSO-d₆) δ: 14.15 and 13.84 (two brs, 1H), 11.92 (brs, 1H),11.57 and 11.14 (two brs, 1H), 9.93 (s, 1H), 8.58 and 8.53 (s, 1H),7.98-7.07 (m, 5H), 6.37 (dd, J=1.6, 8.5 Hz, 1H), 6.32 (s, 1H)

Mass, m/z: 390 (M⁺), 239 (base)

Examples 21-2 to 21-25

The objective compounds were obtained according to the same procedure asin Example 21-1 except that carbonyl compounds or carboxylic acids shownin the following tables were used instead of 2,4-dihydroxybenzaldehydeor 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid.

TABLE 153 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/z3,4-Dihydroxy benzaldehyde —

(DMSO-d₆) δ: 11.65 (brs, s, 1H), 9.32 (brs, s, 1H), 8.30 (s, 1H),7.90-7.66 (m, 3H), 7.60- 7.48 (m, 1H), 7.25 (s, 1H), 6.94 (d, J = 8.1Hz, 1H), 6.79 (d, J = 8.1 Hz, 1H) 390 (M⁺), 239 (base) 2,5-Dihydroxybenzaldehyde —

(DMSO-d₆) δ: 14.19 and 13.88 (two brs, 1H), 12.01 (brs, s, 1H), 10.49and 10.09 (two brs, 1H), 8.97 (s, 1H), 8.63 and 8.61 (two s, 1H),7.96-7.47 (m, 3H), 7.20- 6.68 (m, 3H), 6.75 (s, 1H) 390 (M⁺), 239 (base)2,3-Dihydroxy benzaldehyde —

(DMSO-d₆) δ: 14.22 and 13.89 (two brs, 1H), 12.14 (brs, 1H), 11.33 and10.73 (two brs, 1H), 9.28 and 9.13 (two s, 1H), 8.68 and 8.62 (two s,1H), 7.97-7.46 (m, 3H), 7.20-6.68 (m, 4H) 390 (M⁺), 239 (base)

TABLE 154 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/z3,5- Dihydroxy benzaldehyde —

(DMSO-d₆) δ: 14.16 and 13.83 (two brs, 1H), 11.79 and 11.65 (two brs,1H), 9.44 (s, 2H), 8.33 and 8.25 (two s, 1H), 8.01-7.42 (m, 4H), 6.69-6.51 (m, 2H), 6.33-6.22 (m, 1H) 390 (M⁺), 239 (base) 4-Hydroxy-3-methoxy benzaldehyde —

(DMSO-d₆) δ: 13.99 (brs, 1H), 11.64 (brs, 1H), 9.53 (brs, 1H), 8.38 (s,1H), 7.92-7.68 (m, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.31 (s, 1H), 7.09 (d,J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 3.85 (s, 3H) 404 (M⁺), 149(base) 4-Hydroxy- 3-methyl benzaldehyde —

(DMSO-d₆) δ: 14.30-13.6 (brs, 1H), 11.69 and 11.53 (two brs, 1H), 9.83(s, 1H), 8.34 (s, 1H), 8.06-7.28 (m, 5H), 6.85 (d, J = 8.5 Hz, 1H), 2.17(s, 3H) 388 (M⁺), 150 (base) 2-Chloro- 4-hydroxy benzaldehyde —

(DMSO-d₆) δ: 13.98 (brs, 1H), 11.91 (s, 1H), 10.40 (s, 1H), 8.78 (s,1H), 8.01-7.61 (m, 3H), 7.56 (d, J = 8.1 Hz, 1H), 6.91-6.80 (m, 2H) 408(M⁺), 239 (base)

TABLE 155 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/z3-Hydroxy- 4-methoxy benzaldehyde —

(DMSO-d₆) δ: 14.01 (brs, 1H), 11.67 (s, 1H), 9.29 (s, 1H), 8.34 (s, 1H),7.97-7.64 (m, 2H), 7.56 (d, J = 7.3 Hz, 1H), 7.28 (s, 1H), 7.06 (d, J =8.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H) 404 (M⁺), 239 (base)4-Hydroxy-2- methoxy benzaldehyde —

(DMSO-d₆) δ: 13.96 (brs, 1H), 11.68 (s, 1H), 9.99 (s, 1H), 8.69 (s, 1H),7.97-7.47 (m, 3H), 6.52-6.41 (m, 2H), 3.81 (s, 3H) 404 (M⁺), 135 (base)4-Hydroxy- 3,5- dimethyl benzaldehyde —

(DMSO-d₆) δ: 13.95 (brs, 1H), 11.62 (s, 1H), 8.75 (brs, 1H), 8.31 (s,1H), 7.89-7.70 (m, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.31 (s, 2H), 2.21 (s,6H) 402 (M⁺), 147 (base)

TABLE 156 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/z4-Hydroxy- 3,5- dimethoxy benzaldehyde —

(DMSO-d₆) δ: 14.12 and 13.80 (two s, 1H), 11.77 and 11.59 (two s, 1H),8.93 and 8.86 (two s, 1H), 8.41 and 8.34 (two s, 1H), 7.98-7.48 (m, 3H),7.00 and 6.96 (two s, 2H), 3.83 (s, 6H) 434 (M⁺), 179 (base) 3-Chloro-4-hydroxy benzaldehyde —

(DMSO-d₆) δ: 14.14 and 13.81 (two s, 1H), 11.84 and 11.67 (two s, 1H),10.73 and 10.67 (two s, 1H), 8.41 and 8.32 (two s, 1H), 8.08-7.44 (m,5H), 7.05 (d, J = 7.3 Hz, 1H) 408 (M⁺), 239 (base) 5-Hydroxy- 2-nitrobenzaldehyde —

(DMSO-d₆) δ: 14.08 (brs, 1H), 12.23 (s, 1H), 11.10 (brs, 1H), 9.01 (s,1H), 8.07 (d, J = 8.9 Hz, 1H), 7.89-7.70 (m, 2H), 7.57 (d, J = 8.1 Hz,1H), 7.49 (d, J = 2.3 Hz, 1H), 6.98 (dd, J = 2.7, 8.9 Hz, 1H) 419 (M⁺),239 (base)

TABLE 157 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 21-15 3-Hydroxy- 4-nitro benzaldehyde —

(DMSO-d₆) δ : 14.24 and 13.89 (two s, 1H), 12.13 and 12.02 (two s, 1H),11.16 (s, 1H), 8.52 and 8.42 (two s, 1H), 7.99 (d, J = 8.5Hz, 1H),7.93-7.08 (m, 5H) 419 (M⁺), 239 (base) Example 21-16 4-Hydroxy- 3-nitrobenzaldehyde —

(DMSO-d₆) δ : 14.17 and 13.83 (two s, 1H),, 11.97 and 11.82 (two s, 1H),11.47 (s, 1H), 8.50 and 8.41 (two s, 1H), 8.22 and 8.16 (two s, 1H),7.99-7.48 (m, 4 H), 7.22 (d, J = 8.5Hz, 1H) 419 (M⁺), 239 (base) Example21-17 3,5-Di-tert- butyl-4- hydroxy benzaldehyde —

(DMSO-d₆) δ : 14.10 and 13.79 (two s, 1H), 11.67 and 11.46 (two s, 1H),8.45 and 8.39 (two s, 1H), 8.10-7.36 (m, 7H), 1.42 (s, 18H) 486 (M⁺),216 (base)

TABLE 158 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 21-18 3-Fluoro- 4-hydroxy benzaldehyde —

(DMSO-d₆) δ : 14.14 and 13.81 (two s, 1H), 11.82 and 11.65 (two s, 1H),10.40 and 10.34 (two s, 1H), 8.42 and 8.33 (two s, 1H), 8.07-6.97 (m,6H) 392 (M⁺), 239 (base) Example 21-19 4-Methoxy benzaldehyde —

(DMSO-d₆) δ : 14.14 and 13.81 (two brs, 1H), 11.79 and 11.61 (two s,1H), 8.48 and 8.39 (two s, 1H), 7.98- 7.10 (m, 6H), 7.03 (dd, J = 6.9,6.2Hz, 2H), 3.82 (s, 3H) 388 (M⁺), 150 (base) Example 21-20 3-Hydroxy-4-methoxy benzaldehyde 5-(4- Chloro phenyl)- 2H- pyrazole- 3- carboxylicacid

(DMSO-d₆) δ : 13.92 and 13.80 (two s, 1H), 11.71 and 11.51 (two s, 1H),9.30 and 9.26 (two s, 1H), 8.38 and 8.28 (two s, 1H), 7.87 (d, J =8.5Hz, 1H), 7.82 and 7.52 (two d, J = 8.5Hz, 1H), 7.57 (d, J = 8.5Hz, 1H), 7.46-7.27 (m, 1H), 7.25 (dd, J = 1.5, 8.1Hz, 1H), 7.10 and 7.03 (twodd, J = 1.6, 8.5Hz, 1H), 6.98 (t, J = 7.7, 8.1Hz. 1H), 3.82 and 3.81(two s, 3H) 370 (M⁺), 205 (base) Example 21-21 4-Hydroxy- 3,5-dimethylbenzaldehyde 5-(4- Chloro phenyl)- 2H- pyrazole- 3- carboxylic acid

(DMSO-d₆) δ : 13.89 and 13.80 (two brs, 1H), 11.67 and 11.47 (two brs,1H), 8.70 and 8.35 (two s, 1H), 7.85 (s, 2H), 7.55 (s, 2H), 7.40- 7.19(m, 3H), 2.21 (s, 6H) 368 (M⁺), 148 (base)

TABLE 159 Carbonyl Carboxylic Mass, compound acid Example ¹H-NMR m/zExample 21-22 3-Hydroxy- 4-methoxy benzaldehyde 2-Methyl- 5-phenyl- 2H-pyrazole- 3- carboxylic acid

(DMS0-d₆) δ : 11.73 (s, 1H), 9.30 (s, 1H), 8.28 (s, 1H), 7.80 (d, J =7.7Hz, 2H), 7.45 (dd, J = 7.3, 8.1Hz, 2H). 7.34 (dd, J = 5.8, 8.9Hz,2H), 7.28 (d, J = 1.5Hz, 1H), 7.08 (dd, J = 1.5, 8.5Hz, 1H), 6.99 (d, J= 8.1Hz, 1H), 4.13 (s, 3H), 3.82 (s, 3H) 350 (M⁺), 185 (base) Example21-23 4-Hydroxy- 3,5-dimethyl benzaldehyde 2-Methyl- 5-phenyl- 2H-pyrazole- 3- carboxylic acid

(DMSO-d₆) δ : 11.70 (s, 1H), 8.76 (s, 1H), 8.25 (s, 1H), 7.80 (d, J =7.3Hz, 2H), 7.45 (dd, J = 7.3, 8.1Hz, 2H), 7.37- 7.31 (m, 4H), 4.13 (s,3H), 2.22 (s, 6H) 348 (M⁺), 201 (base) Example 21-24 4′-Hydroxy aceto-phenone —

(DMSO-d₆) δ : 14.00 (brs, 1H), 10.91 and 10.48 (two brs, 1 H), 9.79 (s,1H), 8.04- 7.45 (m, 5H), 6.82 (d, J = 7.7Hz, 1H), 2.31 (s, 3H) 388 (M⁺),150 (base) Example 21-25 1-Methyl- 1H- benzimida- zole-5- carboxy-aldehyde Example 3-2

(DMSO-d₆) δ : 11.86 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.96- 7.92 (m,1H), 7.79 (d, J = 8.5Hz, 1H), 7.67 (d, J = 8.1Hz, 1H), 7.46 (s, 1H),7.23 (d, J = 1.5Hz, 1H), 7.09 (dd, J = 1.9, J = 8.5Hz, 1H), 4.16 (s,3H), 3.97 (s, 3H), 3.88 (s, 3H) 422 (M⁺), 249 (base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom, an alkyl group, or an alkoxy group), and R′represents an aryl or heterocyclic group which may have a substituent(such as an alkyl group, a hydroxyl group, or an alkoxy group).

Example 22-1 Step 22-1-1 Methyl 4-(2-chlorophenyl)-2,4-dioxobutyrate

In dimethylformamide (22 ml), 1-(2-chlorophenyl)ethanone (3.56 g) anddimethyl oxalate (3.26 g) were dissolved, and 60% sodium hydridesuspension in oil (1.1 g) was added thereto while stirring at 5° C. Themixture was heated at a room temperature for one hour and then at 50° C.for 30 minutes. After being allowed to cool, the mixture was acidifiedwith 2-N hydrochloric acid, and the precipitated crystal was separatedby filtration, washed with water, and dried to give the title compound(3.83 g, 69%).

Mass, m/z: 240 (M⁺), 181 (base)

Step 22-1-2 Methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate

In ethanol (8 ml), methyl 4-(2-chlorophenyl)-2,4-dioxobutyrate (1.2 g)obtained in the Step 22-1-1 and hydrazine monohydrate (0.25 g) wereheated under reflux for 11 hours while stirring. After the mixture wasallowed to cool, the precipitated crystal was separated by filtrationand dried to give the title compound (617 mg, 52%).

Mass, m/z: 236 (M⁺), 148 (base)

Step 22-1-3 5-(2-Chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide

In ethanol (10 ml), methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate(135 mg) obtained in the Step 22-1-2 and hydrazine monohydrate (429 mg)were heated under reflux for 9 hours. The mixture was concentrated undera reduced pressure, and water was added thereto. The precipitatedcrystal was separated by filtration and dried to give the title compound(116 mg, 86%).

¹H-NMR (DMSO-d₆) δ: 13.67 (brs, 1H), 9.79 (brs, 1H), 7.74 (s, 1H), 7.60(d, J=6.2 Hz, 1H), 7.50-7.00 (m, 3H), 4.47 (brs, 2H)

Mass, m/z: 236 (M⁺), 205 (base)

Step 22-1-4 5-(2-Chlorophenyl)-2H-pyrazole-3-carboxylic acid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

In ethanol (3 ml), 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acidhydrazide (30 mg) prepared in the Step 22-1-3 and3-hydroxy-4-methoxybenzaldehyde (25 mg) was heated under reflux for 24hours. After the mixture was allowed to cool, the precipitated crystalwas separated by filtration and dried to give the title compound (32 mg,68%).

¹H-NMR (DMSO-d₆) δ: 14.04 (and 13.74 (two s, 1H), 11.73 and 11.55 (twos, 1H), 9.30 and 9.27 (two s, 1H), 8.39 and 8.30 (two s, 1H), 7.73-7.60(m, 1H), 7.60-7.36 (m, 3H), 7.32-7.24 (m, 1H), 7.14-6.95 (m, 3H), 3.82and 3.81 (two s, 3H)

Mass, m/z: 370 (M⁺), 205 (base)

Examples 22-2 to 22-10

The objective compounds were obtained according to the same procedure asin Example 22-1 except that any one of aldehyde compounds or any one ofketone compounds shown in the following tables were used instead of3-hydroxy-4-methoxybenzaldehyde or 1-(2-chlorophenyl)ethanone.

TABLE 160 Aldehyde Ketone Mass, compound compound Example ¹H-NMR m/zExample 22-2 4-Hydroxy- 3-methyl benzaldehyde —

(DMSO-d₆) δ : 14.02 and 13.72 (two s, 1H), 11.68 and 11.49 (two s, 1H),9.86 and 9.79 (two s, 1H), 8.39 and 8.31 (two s, 1H), 8.06-7.00 (m, 7H),6.85 (d, J = 7.3Hz, 1H), 2.17 (s, 3H) 354 (M⁺), 205 (base) Example 22-3— 1-(2-Methyl phenyl) ethanone

(DMSO-d₆) δ : 13.52 (s, 1H), 11.50 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1H),7.64-6.88 (m, 8H), 3.81 (s, 3H), 2.39 (s, 3H) 350 (M⁺), 185 (base)Example 22-4 4-Hydroxy- 3-methyl benzaldehyde 1-(2-Methyl phenyl)ethanone

(DMSO-d₆) δ : 13.50 (s, 1H), 11.45 (s, 1H), 9.78 (s, 1H), 8.38 (s, 1H),7.70-6.88 (m, 7H), 6.85 (d, J = 8.1 Hz, 1 H), 2.39 (s, 1.8H), 2.17 (s,3H) 334 (M⁺), 185 (base) Example 22-5 4-Hydroxy- benzaldehyde1-(2-Methyl phenyl) ethanone

(DMSO-d₆) δ : 13.51 (s, 1H), 11.47 (s, 1H), 9.87 (s, 1H), 8.42 (s, 1H),7.66-6.88 (m, 7H), 6.84 (d, J = 8.1 Hz, 2 H), 2.39 (s, 3H) 320 (M⁺), 185(base)

TABLE 161 Aldehyde Ketone Mass, compound compound Example ¹H-NMR m/zExample 22-6 4-Hydroxy- 3,5- dimethyl benzaldehyde 1-(2- Methoxy phenyl)ethanone

(DMSO-d₆) δ : 13.40 (s, 1H), 11.38 (s, 1H), 8.69 (s, 1H), 8.35 (s, 1H),7.75 (dd, J = 1.5Hz, J = 7.7Hz, 1H), 7.40 (dt, J = 1.5Hz, J = 7.7Hz,1H), 7.33 and 7.29 (two s, 2H), 7.19 (d, J = 7.7Hz, 1H), 7.14 and 7.13(two s, 1H), 7.07 (dt, J = 0.8Hz, J = 7.7Hz, 1H), 3.93 (s, 3H), 2.22(two s, 6H) 364 (M⁺), 201 (base) Example 22-7 — 1-(2- Methoxy phenyl)ethanone

(DMSO-d₆) δ : 13.47 (s, 1H), 11.43 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1H),7.75 (dd, J = 1.5Hz, J = 7.7Hz, 1H), 7.40 (t, J = 7.7Hz, 1H), 7.27 (s,1H), 7.19 (d, J = 7.7Hz, 1H), 7.14 (s, 1H), 7.07 (t, J = 7.7Hz. 1H),7.04 (d, J = 8.5Hz, 1H), 6.98 (d, J = 8.1Hz, 1H), 3.93 (s, 3 H), 3.82(s, 3H) 366 (M⁺), 201 (base) Example 22-8 — 1-(4- Chloro- 2-methoxyphenyl) ethanone

(DMSO-d₆) δ : 13.48 (s, 1H), 11.45 (s, 1H), 9.27 (s, 1H), 8.38 (s, 1H),7.77 (d, J = 8.1Hz, 1H), 7.31-7.11 (m, 2 H), 7.18-7.00 (m, 2H), 7.09 (d,J = 8. 9Hz, 1H), 7.03 (d, J = 8.9Hz, 1H), 6.98 (d, J = 8.5Hz, 1H), 3.96(s, 3H), 3.82 (s, 3H) 400 (M⁺), 251 (base)

TABLE 162 Aldehyde Ketone Mass, compound compound Example ¹H-NMR m/zExample 22-9 4-Hydroxy- 3,5- dimethyl benzadehyde 1-(4- Chloro-2-methoxy phenyl) ethanone

(DMSO-d₆) δ : 13.86 and 13.47 (two s, 1H), 11.67 and 11.40 (two s, 1H),8.69 and 8.76 (two s, 1H), 8.35 and 8.29 (two s, 1H), 7.95 (d, J =7.7Hz, 1H), 7.77 (d, J = 8.5Hz, 1H), 7.33 and 7.29 (two s, 2 H), 7.27(d, J = 1.9Hz, 1H), 7.18-7.12 (m, 1H), 3.96 (s, 3H), 2.21 (s, 6H) 398(M⁺), 235 (base Example 22-10 1-Methyl- 1H- benzimida- zole-5- carboxy-aldehyde 1-(4- Chloro-2- methoxy phenyl) ethanone

(DMSO-d₆) δ : 11.55 (s, 1H), 8.64 (s, 1H), 8.25 (s, 1H), 7.97- 7.92 (m,1H), 7.89 (s, 1H), 7.80-7.75 (m, 2H), 7.66 (d, J = 8.1Hz, 1H), 7.28 (d,J = 1.9Hz, 1H), 7.18~ 7.14 (m, 2H), 3.97 (s, 3H), 3.88 (s, 3H) 407 (M⁺),251 (base)

In the formulae, R represents an alkyl group, or a carbocyclic(homocyclic) or heterocyclic group which may have a substituent (such asa halogen atom, an alkyl group, a haloalkyl group, a hydroxyl group, oran alkoxy group); R′ represents a hydrogen atom, an alkyl group, ahaloalkyl group, or a cycloalkyl or aryl group which may have asubstituent (such as an alkoxy group); and R″ represents a carbocyclic(homocyclic) or heterocyclic group which may have a substituent (such asa halogen atom, an alkyl group, a hydroxyl group, an alkoxy group, anaryloxy group, an aralkyloxy group, an alkylthio group, an amino group,an N-alkyl-substituted amino group, or a nitro group).

Example 23-1 Step 23-1-1 Ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate

In ethanol (10 ml), 2,4-dichlorothiobenzamide (378 mg) was dissolved,and ethyl 2-chloroacetoacetate (302 mg) was added thereto. The mixturewas heated under reflux for 25 hours. After the mixture was allowed tocool, the precipitated crystal was separated by filtration, washed withwater, and dried to give ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (368 mg, 64%).

¹H-NMR (CDCl₃) δ: 8.08 (d, J=1.9 Hz, 1H), 7.76 (dd, J=2.0, 8.5 Hz, 1H),7.51 (d, J=8.1 Hz, 1H), 4.35 (q, J=7.3 Hz, 2H), 1.38 (t, J=7.3 Hz, 3H)

Mass, m/z: 315 (M⁺), 71 (base)

Step 23-1-2 2-(2,4-Dichlorophenyl)-4-methylthiazole-5-carboxylic acidhydrazide

Ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate (250 mg)prepared in the Step 23-1-1 was dissolved in ethanol (10 ml), andhydrazine monohydrate (794 mg) was added thereto. The mixture was heatedunder reflux for 23 hours. After the mixture was allowed to cool, theprecipitated crystal was separated by filtration, washed with water, anddried to give 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acidhydrazide (211 mg, 88%).

¹H-NMR (DMSO-d₆) δ: 9.62 (brs, 1H), 8.13 (d, J=1.9 Hz, 1H), 7.89 (dd,J=2.3, 8.5 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 4.56 (brs, 2H), 2.60 (s, 3H)

Mass, m/z: 301 (M⁺), 71 (base)

Step 23-1-3 2-(2,4-Dichlorophenyl)-4-methylthiazole-5-carboxylicacid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

In ethanol (5 ml), 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylicacid hydrazide (34 mg) and 3-hydroxy-4-methoxybenzaldehyde (19 mg) washeated under reflux for 25 hours. After the mixture was allowed to cool,the precipitated crystal was separated by filtration to give the titlecompound (42 mg, 86%).

¹H-NMR (DMSO-d₆) δ: 11.74 (s, 1H), 9.39 (s, 1H), 8.21 (s, 1H), 8.00 (d,J=7.3 Hz, 1H), 7.99 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.31 (s, 1H), 7.09(dd, J=1.5, 8.5 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 3.82 (s, 3H), 2.77 (s,3H)

Mass, m/z: 435 (M⁺), 71 (base)

Examples 23-2 to 23-165 and 23-171 to 23-172

The objective compounds were obtained according to the same procedure asin Example 23-1 except that compounds shown in the following tables wereused instead of 2,4-dichlorothiobenzamide as a thioamide compound,3-hydroxy-4-methoxybenzaldehyde as an aldehyde compound, or ethyl2-chloroacetoacetate as a ring-forming component.

TABLE 163 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-2 2-Chloro thio- benzamide — —

(DMSO-d₆) δ : 11.75 (s, 1H), 9.11 (s, 1H), 8.39-8.20 (m, 1 H), 7.99 (s,1H), 7.72- 7.67 (m, 1H), 7.59-7.51 (m, 2H), 7.30 (s, 1H), 7.14 (d, J =7.7Hz, 1H), 6.99 (d, J = 8.5Hz, 1H), 3.83 (s, 3H), 2.80 (s, 3H) 401(M⁺), 71 (base) Example 23-3 2-Chloro thio- benzamide 4-Hydroxy-3-methyl benzaldehyde —

(DMSO-d₆) δ : 11.71 (s, 1H), 9.89 (s, 1H), 8.43-8.34 (m, 1 H), 8.00 (s,1H), 7.75- 7.68 (m, 1H), 7.59 (s, 1 H), 7.58-7.51 (m, 2H), 7.40 (dd, J =0.8, 7.7Hz, 1 H), 6.84 (d, J = 8.5Hz, 1H), 2.81 (s, 3H), 2.17 (s, 3H)385 (M⁺), 71 (base) Example 23-4 2-Chloro thio- benzamide 2-Chloro-3-hydroxy- 4-methoxy benzaldehyde —

(DMSO-d₆) δ : 11.95 (s, 1H), 9.63 (s, 1H), 8.47 (s, 1H), 8.37- 8.27 (m,1H), 7.72- 7.68 (m, 1H), 7.63-7.52 (m, 3H), 7.04 (d, J = 8.9Hz, 1H),3.89 (s, 3H), 2.80 (s, 3H) 435 (M⁺), 71 (base) Example 23-5 2-Chlorothio- benzamide 3-Hydroxy- 4,5-dimethoxy benzaldehyde —

(DMSO-d₆) δ : 11.85 (s, 1H), 9.31 (s, 1H), 8.31-8.25 (m, 2 H), 7.98 (s,1H), 7.71- 7.66 (m, 1H), 7.59-7.51 (m, 2H), 6.93 and 6.89 (two s, 1H),3.80 (s, 3 H), 3.72 (s, 3H), 2.80 (s, 3H) 431 (M⁺), 71 (base)

TABLE 164 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-6 4-Chloro thio- benzamide4-Hydroxy benzaldehyde −

(DMSO-d₆) δ : 11.68 (s, 1H), 9.95 (s, 1H), 8.04 (d, J = 8.1Hz, 2H), 8.03(s, 1H), 7.61 (dt, J = 1.9, 2.7, 8.5Hz, 4H), 6.88 (d, J = 8.1Hz, 2H),2.77 (s, 3H) 371 (M⁺), 71 (base) Example 23-7 4-Chloro thio- benzamide −−

(DMSO-d₆) δ : 11.69 (s, 1H), 9.37 (s, 1H), 8.05 (d, J = 7.7Hz, 2H), 7.99(s, 1H), 7.61 (dt, J = 1.9, 2.3, 8.8Hz, 2H), 7.28 (d, J = 1.9Hz, 1H),7.10 (d, J = 8.1Hz, 1H), 7.01 (d, J = 8.5Hz, 1H), 3.82 (s, 3H), 2.77 (s,3H) 401 (M⁺), 71 (base) Example 23-8 4-Chloro thio- benzamide 4-Hydroxy-3,5-dimethyl benzaldehyde −

(DMSO-d₆) δ : 11.68 (s, 1H), 8.78 (s, 1H), 8.01 (d, J = 8.1Hz, 2H), 7.96(s, 1H), 7.62 (d, J = 8.1Hz, 2H), 7.36 (s, 2H), 2.22 (s, 6H) 399 (M⁺),71 (base) Example 23-9 4-Chloro thio- benzamide 3-Hydroxy benzaldehyde −

(DMSO-d₆) δ : 11.81 (s, 1H), 9.68 (s, 1H), 8.05 (s, 1H), 8.04 (d, J =7.0Hz, 2H), 7.62 (dt, J = 1.9, 2.7, 8.5Hz, 2H), 7.29 (dd, J = 7.7,8.1Hz, 1H), 7.20 (dd, J = 1.6, 2.3Hz, 1H), 7.14 (d, J = 7.3Hz, 1H), 6.85(ddd, J = 1.2, 2.7, 8.1Hz, 1H), 2.77 (s, 3H) 371 (M⁺), 71 (base)

TABLE 165 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-10 4-Chloro thio- benzamide3,4-Dihydroxy benzaldehyde −

(DMSO-d₆) δ : 11.62 (s, 1H), 9.41 (s, 1H), 9.33 (s, 1H), 8.06 (d, J =8.1Hz, 2H), 7.95 (s, 1H), 7.61 (dt, J = 1.9, 2.7, 8.5Hz, 2H), 7.25 (d, J= 1.9Hz, 1H), 6.97 (d, J = 7.7Hz, 1H), 6.82 (d, J = 8.1Hz, 1H), 2.77 (s,3H) 387 (M⁺), 71 (base) Example 23-11 4-Chloro thio- benzamide4-hydroxy- 3-methyl benzaldehyde −

(DMSO-d₆) δ : 11.67 (s, 1H), 9.87 (s, 1H), 8.03 (d, J = 8.1Hz, 2H), 7.99(s, 1H), 7.62 (d, J = 8.5Hz, 2H), 7.50 (s, 1H), 7.43 (d, J = 7.3Hz, 1H),6.88 (d, J = 8.1Hz, 1H), 2.77 (s, 3H), 2.18 (s, 3H) 385 (M⁺), 71 (base)Example 23-12 2-Methyl thio- benzamide − −

(DMSO-d₆) δ : 11.68 (s, 1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.89 (d, J =7.4Hz, 1H), 7.47- 7.34 (m, 3H), 7.25 (d, J = 1.6Hz, 1H), 7.09 (d, J =8.1Hz, 1H), 6.99 (d, J = 8.1Hz, 1H), 3.81 (s, 3H), 2.79 (s, 3H), 2.61(s, 3 H) 381 (M⁺), 216 (base) Example 23-13 2-Trifluoro methyl thio-benzamide − −

(DMSO-d₆) δ : 11.74 (s, 1H), 9.21 (s, 1H), 8.01-7.94 (m, 2 H), 7.87-7.76(m, 3H), 7.18 (s, 1H), 7.08 (dd, J = 1.9, 8.5Hz, 1H), 6.97 (d J = 8.5Hz,1H), 3.79 (s, 3H), 2.78 (s, 3H) 435 (M⁺), 71 (base)

TABLE 166 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-14 2-Methoxy thio- benzamide — —

(DMSO-d₆) δ : 11.59 (s, 1H), 9.16 (brs, 1H), 8.37 (d, J = 7.7 Hz, 1H),7.99 (brs, 1H), 7.55-7.49 (m, 1H), 7.35- 7.26 (m, 2H), 7.21-7.09 (m,2H), 7.03 (d, J = 7.7 Hz, 1H), 4.10 (s, 3H), 3.84 (s, 3H), 2.78 (s, 3H)397 (M⁺), 232 (base) Example 23-15 2,3- Dichloro thio- benzamide — —

(DMSO-d₆) δ : 11.78 (s, 1H), 9.15 (brs, 1H), 8.27 (d, J = 7.7 Hz, 1H),8.00 (s, 1H), 7.84 (dd, J = 1.6, 8.1Hz, 1 H), 7.56 (t, J = 8.1Hz, 1H),7.30 (s, 1H), 7.11 (d, J = 7.7Hz, 1H), 7.00 (d, J = 8.5Hz, 1H), 3.82 (s,3 H), 2.80 (s, 3H) 435 (M⁺), 71 (base) Example 23-16 4-Chloro thio-benzamide — Ethyl 2- chloro-3- oxo- propionate

(DMSO-d₆) δ : 11.90 (s, 1H), 9.45 (s, 1H), 8.69 (s, 1H), 8.32- 7.98 (m,3H), 7.69-7.57 (m, 2H), 7.34 (d, J = 0.8Hz, 1H), 7.13 (dd, J = 1.6,8.5Hz, 1H), 7.03 (d, J = 8.1Hz, 1H), 3.83 (s, 3H) 387 (M⁺), 57 (base)Example 23-17 4-Chloro thio- benzamide 4-Hydroxy- 3,5- dimethylbenzalde- hyde Ethyl 2- chloro-3- oxo- propionate

(DMSO-d₆) δ : 11.88 (s, 1H), 8.82 (s, 1H), 8.28-7.98 (m, 3 H), 7.69-7.58(m, 2H), 7.39 (d, 2H), 2.25 (s, 6H) 385 (M⁺), 57 (base)

TABLE 167 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-18 4-Chloro thio- benzamide —Ethyl 2- chloro- 4,4,4- trifluoro- 3- oxo- butyrate

(DMSO-d₆) δ : 12.22 (s, 1H), 9.27 (s, 1H), 8.17-7.98 (m, 1 H), 8.08 (d,J = 8.9Hz, 2H), 7.66 (dt, J = 1.9, 2.3, 8.8Hz, 2H), 7.13-6.93 (m, 3H),3.79 (s, 3H) 455 (M⁺), 149 (base) Example 23-19 4-Chloro thio- benzamide4-Hydroxy- 3,5- dimethyl benzaldehyde Ethyl 2- chloro- 4,4,4- trifluoro-3- oxo- butyrate

(DMSO-d₆) δ : 12.18 and 12.14 (two s, 1H), 8.83 and 8.79 (two s, 1H),8.14-7.97 (m, 3H), 7.69-7.63 (m, 2H), 7.34 and 7.22 (two s, 2H), 2.21and 2.16 (two s, 6H) 453 (M⁺), 147 (base) Example 23-20 4-Chloro thio-benzamide 4-Hydroxy- 3,5- dimethyl benzaldehyde Ethyl 2- chloro- 4,4-dimethyl- 3- oxo- pentanoate

(DMSO-d₆) δ : 9.33 (s, 1H), 8.22- 7.25 (m, 1H), 7.89 (d, J = 6.6Hz, 2H),7.40 (dt, J = 1.9, 2.3, 8.5Hz, 2H), 7.29- 6.77 (m, 3H), 5.62 (s, 1H),3.91 (s, 3H), 1.49 (s, 9H) 443 (M⁺), 278 (base)

TABLE 168 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-21 4-Chloro thio- benzamide 4-Hydroxy- 3,5- dimethyl benz- aldehyde Methyl 2- Chloro- 4,4- dimethyl-3-oxo- pentanoate

(DMSO-d₆) δ : 11.91 (brs, 1H), 8.77 (s, 1H), 8.10 (s, 1H), 7.97 (d, J =8.5Hz, 2H), 7.59 (d, J = 8.5Hz, 2H), 7.30 (s, 2H), 2.20 (s, 6H), 1.42(s, 9H) 441 (M⁺), 278 (base) Example 23-22 2,3- Dimethyl thio- benzamide— —

(DMSO-d₆) δ : 11.65 (s, 1H), 9.25 (s, 1H), 7.98 (s, 1H), 7.50 (d, J =7.3Hz, 1H), 7.35 (d, J = 7.3Hz, 1H), 7.24 (t, J = 7.3, 7.7Hz, 1H), 7.21(s, 1H), 7.07 (dd, J = 2.0, 8.1Hz, 1H), 6.99 (d, J = 8.5Hz, 1H), 3.80(s, 3H), 2.78 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H) 395 (M⁺), 230 (base)Example 23-23 2,3- Dimethyl thio- benzamide 4- Hydroxy- 3,5- dimethylbenz- aldehyde —

(DMSO-d₆) δ : 11.65 (s, 1H), 8.76 (s, 1H), 7.96 (s, 1H), 7.58 (d, J =7.3Hz, 1H), 7.35 (d, J = 7.7Hz, 1H), 7.32 (s, 2H), 7.25 (t, J = 7.4,7.7Hz, 1H), 2.78 (s, 3 H), 2.47 (s, 3H), 2.35 (s, 3H), 2.19 (s, 6H) 393(M⁺), 230 (base) Example 23-24 2,3- Dimethyl thio- benzamide — —

(DMSO-d₆) δ : 11.62 (s, 1H), 9.09 (s, 1H), 8.00 (s, 1H), 7.89 (d, J =4.2Hz, 1H), 7.27 (d, J = 1.9Hz, 1H), 7.23 (s, 1H), 7.21 (d, J = 1.2Hz,1H), 7.20-7.14 (m, 1 H), 7.01 (d, J = 8.1Hz, 1H), 4.00 (s, 3H), 3.90 (s,3H), 3.84 (s, 3H), 2.76 (s, 3H) 427 (M⁺), 262 (base)

Table 169 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-25 2,3- Dimethoxy thio-benzamide 4-Hydroxy- 3,5- dimethyl benz- aldehyde —

(DMSO-d₆) δ : 11.58 (s, 1H), 8.76 (s, 1H), 7.97 (s, 1H), 7.95- 7.80 (m,1H), 7.39 (s, 2H), 7.23 (d, J = 0.8Hz, 1 H), 7.22 (s, 1H), 3.94 (s, 3H),3.91 (s, 3H), 2.77 (s, 3H), 2.22 (s, 6H) 425 (M⁺), 262 (base) Example23-26 3-Methyl pyridine-2- carbo- thioamide — —

(DMSO-d₆) δ : 11.66 and 11.61 (two s, 1H), 9.29 and 9.18 (two s, 1H),8.52 (d, J = 4.2Hz, 1H), 8.25 and 7.99 (two s, 1H), 7.83 (d, J = 7.3Hz,1H), 7.44 (dd, J = 4.6, 7.7Hz, 1H), 7.32-6.94 (m, 3H), 3.82 (s, 3H),2.77 (s, 3H), 2.75 and 2.68 (two brs, 2H) 382 (M⁺), 217 (base) Example23-27 Isoquin- oline-1- carbo- thioamide — —

(DMSO-d₆) δ : 11.75 and 11.71 (two s, 1H), 9.79-9.73 (m, 1H), 9.30 and9.20 (two s, 1H), 8.64 (d, J = 5.4Hz, 1H), 8.33-8.00 (m, 3H), 7.92-7.83(m, 2 H), 7.34-7.96 (m, 3H), 3.82 (s, 3H), 2.85 and 2.78 (two s, 3H) 418(M⁺), 253 (base) Example 23-28 Pyridine- 2- carbo- thioamide — —

(DMSO-d₆) δ : 11.69 (s, 1H), 9.21 (s, 1H), 8.68 (d, J = 4.2Hz, 1H),8.32-7.92 (m, 3H), 7.55 (ddd, J = 1.2, 5.0, 7.3Hz, 1H), 7.40-7.04 (m,2H), 7.02 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 2.75 (s, 3H) 368 (M⁺), 203(base)

TABLE 170 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-29 Pyridine- 2- carbo- thioamide4- Hydroxy- 3,5- dimethyl benz- aldehyde —

(DMSO-d₆) δ : 11.68 (s, 1H), 8.77 (s, 1H), 8.70-8.64 (m, 1 H), 8.28-7.89(m, 1H), 8.17 (d, J = 7.7Hz, 1H), 7.98 (td, J = 1.5, 7.7Hz, 1H), 7.55(ddd, J = 0.8, 5.0, 7.4Hz, 1H), 7.40 (s, 2H), 2.78 (s, 3H), 2.23 (s, 6H)366 (M⁺), 203 (base) Example 23-30 4-Chloro thio- benzamide — Methyl 2-chloro-3- oxo- nonanoate

(DMSO-d₆) δ : 11.66 (s, 1H), 9.35 (s, 1H), 8.04 (d, J = 7.7Hz, 2H), 7.99(s, 1H), 7.61 (dt, J = 1.9, 2.3, 8.9Hz, 2H), 7.26 (d, J = 1.9Hz, 1H),7.09 (d, J = 7.4Hz, 1H), 7.00 (d, J = 8.5Hz, 1H), 3.82 (s, 3H), 3.29-3.00 (m, 2H), 1.72 (quintet, J = 7.3Hz, 2H), 1.40- 1.23 (m, 6H), 0.85(t, J = 7.3Hz, 3H) 471 (M⁺), 71 (base) Example 23-31 4-Chloro thio-benzamide 4- Hydroxy- 3,5- dimethyl benz- aldehyde Methyl 2- chloro-3-oxo- nonanoate

(DMSO-d₆) δ : 11.64 (s, 1H), 8.77 (s, 1H), 8.26-7.91 (m, 1 H), 8.01 (d,J = 8.1Hz, 2H), 7.62 (d, J = 8.5Hz, 2 H), 7.35 (s, 2H), 3.29-3.16 (m,2H), 1.72 (quintet, J = 7.3Hz, 2H), 1.42-1.21 (m, 6H), 0.85 (t, J = 6.5,7.0Hz, 3H) 469 (M⁺), 71 (base)

TABLE 171 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Example 23-32 4-Chloro thio- benzamide 2-Furalde- hyde —

(DMSO-d₆) δ : 11.83 (brs, 1H), 8.02 (d, J = 8.5Hz, 2H + 1H), 7.88 (s,1H), 7.61 (dt, J = 1.9, 2.0, 2.3, 8.9Hz, 2 H), 6.99 (d, J = 2.7Hz, 1H),6.77 (dd, J = 1.6, 3.1Hz, 1H), 2.75 (s, 3H) 345 (M⁺), 71 (base) Example23-33 4-Chloro thio- benzamide 3- Furalde- hyde —

(DMSO-d₆) δ : 11.78 (brs, 1H), 8.19 (s, 1H), 8.10-8.00 (m, 3H), 7.80 (s,1H), 7.60 (dt, J = 1.9, 2.7, 8.5Hz, 2 H), 6.91 (s, 1H), 2.77 (s, 3H) 345(M⁺), 71 (base) Example 23-34 4-Chloro thio- benzamide 3,4- (Methylenedioxy) benz- aldehyde —

(DMSO-d₆) δ : 11.79 (brs, 1H), 8.04 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H),7.61 (dt, J = 1.6, 1.9, 8.5Hz, 2H), 7.32 (s, 1H), 7.21 (d, J = 8.1Hz,1H), 7.02 (d, J = 7.7Hz, 1H), 6.11 (s, 2H), 2.76 (s, 3H) 399 (M⁺), 71(base) Example 23-35 4-Chloro thio- benzamide 3- Hydroxy- 4-methyl benz-aldehyde —

(DMSO-d₆) δ : 11.74 (brs, 1H), 9.64 (brs, 1H), 8.07 (d, J = 7.3Hz, 2H),8.01 (s, 1H), 7.61 (dt, J = 1.6, 1.9, 2.3, 2.7, 8.5Hz, 2H), 7.25 (s,1H), 7.17 (d, J = 7.7Hz, 1H), 7.03 (d, J = 6.6Hz, 1H), 2.77 (s, 3H),2.16 (s, 3H) 385 (M⁺), 236 (base)

TABLE 172 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2- Methoxy- thio- benzamide 2- Fur-aldehyde —

(DMSO-d₆) δ: 11.72 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 8.00 (br s, 1H),7.90 (br s, 1H), 7.52 (td, J = 1.5, 8.5 Hz, 1H), 7.30 (d, J = 8.5 Hz,1H), 7.13 (t, J = 7.7 Hz, 1H), 6.96 (d, J = 3.1 Hz, 1H), 6.69 (s, 1H),4.08 (s, 3H), 2.75 (s, 3H) 341 (M⁺), 232 (base) Octane- thioamide — —

(DMSO-d₆) δ: 9.11 (br s, 1H), 7.73 (br s, 1H), 7.38 (d, J = 1.9 Hz, 1H),7.16 (d, J = 7.3 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 5.71 (s, 1H), 3.94(s, 3H), 3.00 (d, J = 7.7 Hz, 2H), 2.81 (s, 3H), 1.83 (quintet, J = 7.4,7.7 Hz, 2H), 1.48-1.22 (m, 8H), 0.87 (t, J = 6.6, 7.3 Hz, 3H) 389 (M⁺),224 (base) 1-Benzo- thiophene- 3-carbo- thioamide — —

(DMSO-d₆) δ: 11.70 (s, 1H), 9.32 (s, 1H), 8.75 (d, J = 8.1 Hz, 1H), 8.61(s, 1H), 8.14 (d, J = 8.1 Hz, 1H), 8.01 (s, 1H), 7.61 (t, J = 7.3, 7.7Hz, 1H), 7.52 (td, J = 0.8, 8.1 Hz, 1H), 7.33 (s, 1H), 7.14 (d, J = 7.7Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 3.83 (s, 3H), 2.84 (s, 3H) 423 (M⁺),258 (base) 1-Benzo- thiophene- 3-carbo- thioamide 4- Hydroxy- 3-methyl-benz- aldehyde —

(DMSO-d₆) δ: 11.67 (s, 1H), 9.87 (s, 1H), 8.72 (d, J = 7.7 Hz, 1H), 8.61(s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.02 (s, 1H), 7.62-7.44 (m, 4H), 6.90(d, J = 8.1 Hz, 1H), 2.84 (s, 3H), 2.18 (s, 3H) 407 (M⁺), 258 (base)

TABLE 173 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z Pyridine-4- carbothioamide — —

(DMSO-d₆) δ: 11.78 (s, 1H), 9.40 (s, 1H), 8.76 (dd, J = 1.6, 4.2 Hz,2H), 8.30-7.87 (m, 1H), 7.97 (d, J = 4.6 Hz, 2H), 7.29 (d, J = 2.0 Hz,1H), 7.12 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H),2.80 (s, 3H) 368 (M⁺), 203 (base) Pyridine-3- carbothioamide — —

(DMSO-d₆) δ: 11.72 (s, 1H), 9.41 (s, 1H), 9.22 (s, 1H), 8.73 (dd, J =1.6, 4.6 Hz, 1H), 8.39 (d, J = 7.0 Hz, 1H), 8.00 (s, 1H), 7.59 (dd, J =4.6, 8.1 Hz, 1H), 7.31 (s, 1H), 7.10 (d, J = 7.7 Hz, 1H), 7.02 (d, J =8.5 Hz, 1H), 3.82 (s, 3H), 2.80 (s, 3H) 368 (M⁺), 203 (base) 4-Chloro-thiobenzamide 3,4- Dimethoxy- benzaldehyde —

(DMSO-d₆) δ: 11.81 (s, 1H), 8.05 (br s, 1H), 8.05 (d, J = 7.7 Hz, 2H),8.01 (dt, J = 1.9, 2.0, 2.7, 8.5 Hz, 2H), 7.61 (dt, J = 1.9, 2.0, 2.7,8.5 Hz, 2H), 7.48 (s, 1H), 7.22 (dd, J = 1.9, 8.5 Hz, 1H), 7.05 (d, J =8.1 Hz, 1H), 3.87 (s, 3H), 3.82 (s, 3H), 2.79 (s, 3H) 415 (M⁺),  71(base) 2,3-Dimethyl- thiobenzamide 3,4-Methylene- dioxy- benzaldehyde —

(DMSO-d₆) δ: 11.76 (br s, 1H), 8.03 (s, 1H), 7.49 (d, J = 7.4 Hz, 1H),7.35 (d, J = 7.3 Hz, 1H), 7.29 (d, J = 1.5 Hz, 1H), 7.24 (d, J = 7.7 Hz,1H), 7.17 (dd, J = 1.2, 7.7 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 6.08 (s,2H), 2.76 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H) 393 (M⁺), 230 (base)

TABLE 174 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2,4-Dimethyl- thiobenzamide — —

(DMSO-d₆) δ: 11.65 (s, 1H), 9.23 (s, 1H), 7.97 (s, 1H), 7.80 (d, J = 6.9Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.23 (s, 1H), 7.18 (d, J = 8.1 Hz,1H), 7.09 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.81 (s, 3H),2.77 (s, 3H), 2.59 (s, 3H), 2.35 (s, 3H) 395 (M⁺),  71 (base)2,4-Dimethyl- thiobenzamide 4-Hydroxy- 3-methyl- benz- aldehyde —

(DMSO-d₆) δ: 11.62 (s, 1H), 9.86 (s, 1H), 7.98 (s, 1H), 7.87 (d, J = 7.7Hz, 1H), 7.53 (s, 1H), 7.37 (dd, J = 1.9, 8.5 Hz, 1H), 7.24 (s, 1H),7.18 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 2.78 (s, 3H), 2.63(s, 3H), 2.35 (s, 3H), 2.16 (s, 3H) 379 (M⁺), 230 (base) 4-Chloro-2-methyl- thiobenzamide — —

(DMSO-d₆) δ: 11.70 (s, 1H), 9.25 (s, 1H), 7.98 (s, 1H), 7.94 (d, J = 7.7Hz, 1H), 7.54 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 2.3, 8.5 Hz, 1H), 7.25(d, J = 1.2 Hz, 1H), 7.09 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H),3.81 (s, 3H), 2.79 (s, 3H), 2.62 (s, 3H) 415 (M⁺),  71 (base)4-Chloro-2- methyl- thiobenzamide 4-Hydroxy- 3-methyl- benz- aldehyde —

(DMSO-d₆) δ: 11.67 (s, 1H), 9.87 (s, 1H), 8.30-7.79 (m, 2H), 7.55 (s,1H), 7.52 (s, 1H), 7.44 (dd, J = 1.9, 8.1 Hz, 1H), 7.38 (dd, J = 1.6,8.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 2.79 (s, 3H), 2.66 (s, 3H), 2.16(s, 3H) 399 (M⁺),  71 (base)

TABLE 175 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Propyl- oxythio- benzamide — —

(DMSO-d₆) δ: 11.57 (s, 1H), 9.16 (br s, 1H), 8.35 (d, J = 7.7 Hz, 1H),7.99 (br s, 1H), 7.52-7.45 (m, 1H), 7.27 (d, J = 8.1 Hz, 1H), 7.24 (brs, 1H), 7.11 (td, J = 0.8, 7.7 Hz, 2H), 6.99 (d, J = 8.1 Hz, 1H), 4.26(t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 2.73 (s, 3H), 1.78 (br s, 2H), 0.85(br s, 3H) 425 (M⁺), 260 (base) 2-Propyl- oxythio- benzamide 2-Fur-aldehyde —

(DMSO-d₆) δ: 11.69 (s, 1H), 8.35 (dd, J = 1.6, 7.7 Hz, 1H), 7.84 (s,1H), 7.49 (td, J = 1.6, 8.5 Hz, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.11 (td,J = 0.8, 8.1 Hz, 1H), 6.93 (d, J = 3.1 Hz, 1H), 6.65 (dd, J = 1.6, 3.5Hz, 1H), 4.24 (t, J = 6.5 Hz, 2H), 2.71 (s, 3H), 1.89 (br s, 2H), 0.95(br s, 3H) 369 (M⁺), 260 (base) 2-Methyl- thio- benzamide — Ethyl 2-chloro-3- oxo- propionate

(DMSO-d₆) δ: 11.89 (s, 1H), 9.32 (s, 1H), 8.71 (s, 1H), 8.02 (s, 1H),7.89 (d, J = 7.7 Hz, 1H), 7.50-7.34 (m, 3H), 7.31 (d, J = 2.0 Hz, 1H),7.12 (dd, J = 1.9, 8.5 Hz, 1H) 7.01 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H),2.61 (s, 3H) 367 (M⁺), 174 (base) 2-Methyl- thio- benzamide 4- Hydroxy-3-methyl- benz- aldehyde Ethyl 2- chloro-3- oxo- propionate

(DMSO-d₆) δ: 11.86 (s, 1H), 9.90 (s, 1H), 8.70 (s, 1H), 8.03 (s, 1H),7.97 (d, J = 7.7 Hz, 1H), 7.56 (s, 1H), 7.47-7.35 (m, 4H), 6.87 (d, J =8.1 Hz, 1H), 2.65 (s, 3H), 2.17 (s, 3H) 351 (M⁺), 174 (base)

TABLE 176 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Methylthio- benzamide 3,4- Methylene-dioxy- benz- aldehyde Ethyl 2- chloro-3- oxo- propionate

(DMSO-d₆) δ: 11.98 (s, 1H), 8.71 (s, 1H), 8.08 (s, 1H), 7.91 (d, J = 7.3Hz, 1H), 7.49-7.30 (m, 4H), 7.22 (dd, J = 1.5, 8.1 Hz, 1H), 7.02 (d, J =7.7 Hz, 1H), 6.11 (s, 2H), 2.62 (s, 3H) 365 (M⁺), 174 (base) Thio-benzamide — —

(DMSO-d₆) δ: 11.67 (s, 1H), 9.36 (s, 1H), 8.04 (br s, 2H), 7.99 (s, 1H),7.58-7.53 (m, 3H), 7.28 (d, J = 1.6 Hz, 1H), 7.10 (d, J = 8.1 Hz, 1H),7.02 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 2.77 (s, 3H) 367 (M⁺), 202(base) Thio- benzamide 4-Hydroxy- 3-methyl- benz- aldehyde —

(DMSO-d₆) δ: 11.65 (br s, 1H), 9.86 (s, 1H), 8.10- 7.90 (m, 3H), 7.59-7.47 (m, 5H), 6.88 (d, J = 8.5 Hz, 1H), 2.77 and 2.67 (two s, 3H), 2.18(s, 3H) 351 (M⁺), 202 (base) 2-Propyloxy- thio- benzamide 4-Hydroxy-3,5- dimethyl- benz- aldehyde —

(DMSO-d₆) δ: 11.53 (s, 1H), 8.73 (s, 1H), 8.34 (d, J = 7.7 Hz, 1H), 7.97(s, 1H), 7.52-7.45 (m, 1H), 7.32 (s, 2H), 7.26 (d, J = 8.5 Hz, 1H), 7.12(t, J = 7.3, 7.7 Hz, 1H), 4.21 (s, 2H), 2.73 (s, 3H), 2.19 (s, 6H), 1.75(br s, 2H), 0.84 (s, 3H) 423 (M⁺), 260 (base)

TABLE 177 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Hydroxy- thiobenzamide 4-Hydroxy- 3,5-dimethyl- benz- aldehyde —

(DMSO-d₆) δ: 11.57 (br s, 1H), 11.27 (s, 1H), 8.16 (dd, J = 1.5, 7.7 Hz,1H), 7.96 (br s, 1H), 7.43-7.27 (m, 3H), 7.09 (d, J = 7.7 Hz, 1H), 6.99(d, J = 7.7 Hz, 1H), 2.76 (s, 3H), 2.23 (s, 6H) 381 (M⁺), 218 (base)2-Hydroxy- thiobenzamide 3-Hydroxy- 4-methoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.61 (s, 1H), 11.46 (s, 1H), 8.15 (d, J = 7.7 Hz, 1H),7.98 (br s, 1H), 7.37 (td, J = 1.5, 8.5 Hz, 1H), 7.32-6.98 (m, 3H), 7.07(d, J = 8.1 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H) 3.83 (s, 3H), 2.75 (s, 3H)383 (M⁺), 218 (base) 4-Chloro- thiobenzamide 3-Chloro- 4-hydroxy- benz-aldehyde —

(DMSO-d₆) δ: 11.80 (br s, 1H), 10.74 (s, 1 H), 8.33-7.90 (m, 3H), 7.77(s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.1 Hz, 1H), 7.08 (d, J= 8.1 Hz, 1H), 2.76 (s, 3H), 2.18 (s, 3H) 405 (M⁺),  71 (base) 4-Chloro-thiobenzamide 2-Hydroxy- benz- aldehyde —

(DMSO-d₆) δ: 12.01 and 11.81 (two br s, 1H), 11.08 and 10.06 (two s,1H), 8.62 and 8.46 (two s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.90-7.50 (m,1H), 7.61 (d, J = 8.5 Hz, 2H), 7.28 (s, 1H), 6.94 (t, J = 7.3, 7.7 Hz,2H), 2.76 and 2.70 (two s, 3H) 371 (M⁺),  71 (base)

TABLE 178 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro- thiobenzamide 2-Hydroxy-3-methoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.98 and 11.82 (two br s, 1H), 10.72 and 9.31 (two s, 1H),8.63 and 8.49 (two s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.61 (dt, J = 1.9,2.0, 2.7, 8.5 Hz, 2H), 7.45 and 7.18 (two br s, 1H), 7.04 (d, J = 7.7Hz, 1H), 6.90 (t, J = 7.0, 6.9 Hz, 1H), 3.83 (s, 3H), 2.76 and 2.70 (twos, 3H) 401 (M⁺),  71 (base) 4-Chloro- thiobenzamide 2-Chloro-3-hydroxy-4- methoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.91 (br s, 1H), 9.62 (br s, 1H), 8.47 (s, 1H), 8.03 (d, J= 8.1 Hz, 2H), 7.61 (dt, J = 1.9, 2.0, 2.7, 8.5 Hz, 2H), 7.57 (d, J =7.7 Hz, 1H), 7.15 (d, J = 7.7 Hz, 1H), 3.90 (s, 3H), 2.77 (s, 3H) 435(M⁺),  71 (base) 4-Chloro- thiobenzamide 3,5- Dibromo- 4-hydroxy- benz-aldehyde —

(DMSO-d₆) δ: 11.96 (br s, 1H), 10.46 (br s, 1H), 8.10-7.88 (m, 5H), 7.65(d, J = 8.1 Hz, 2H), 2.77 (s, 3H) 529 (M⁺),  71 (base) 4-Chloro-thiobenzamide 2-Hydroxy- 1-naphth- aldehyde —

(DMSO-d₆) δ: 12.54 (s, 1H), 12.09 (s, 1H), 9.45 (s, 1H), 8.30 (d, J =8.5 Hz, 1H), 8.15-7.79 (m, 4H), 7.62 (d, J = 7.3 Hz, 2H + 1H), 7.42 (t,J = 6.6, 6.9 Hz, 1H), 7.24 (d, J = 8.8 Hz, 1H), 2.74 (s, 3H) 421 (M⁺), 71 (base)

TABLE 179 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro- thio- benzamide 3-Hydroxy-4-nitro- benzaldehyde —

(DMSO-d₆) δ: 12.07 (s, 1H), 11.23 (br s, 1H), 8.19-7.91 (m, 4H), 7.62(d, J = 8.5 Hz, 2H), 7.49 (s, 1H), 7.36 (d, J = 7.3 Hz, 1H), 2.76 (s,3H) 416 (M⁺),  71 (base) 2-Fluoro- thio- benzamide 4-Methoxy-benzaldehyde —

(DMSO-d₆) δ: 11.79 (br s, 1H), 8.32- 8.30 (m, 1H), 8.09 (s, 1H), 7.82(d, J = 8.9 Hz, 1H), 7.74 (d, J = 8.5 Hz, 2H), 7.62-7.58 (m, 1H),7.52-7.47 (m, 1H), 7.44- 7.40 (m, 1H), 7.07-7.04 (m, 2H), 3.83 (s, 3H),2.81 (s, 3H) 369 (M⁺),  220,  71 (base) 3-Fluoro- thio- benzamide4-Methoxy- benzaldehyde —

(DMSO-d₆) δ: 11.78 (br s, 1H), 8.09 (s, 1H), 7.87 (d, J = 7.6 Hz, 1H),7.82 (d, J = 8.9 Hz, 2H), 7.73 (d, J = 8.1 Hz, 1H), 7.64-7.59 (m, 1H),7.44-7.39 (m, 1H), 7.09-7.05 (m, 2H), 3.83 (s, 3H), 2.78 (s, 3H) 369(M⁺), 220 (base) 4-Fluoro- thio- benzamide 4-Methoxy- benzaldehyde —

(DMSO-d₆) δ: 11.74 (br s, 1H), 8.64 (s, 1H), 8.08 (br s, 2H), 7.72 (d, J= 8.1 Hz, 2H), 7.41-7.37 (m, 2H), 7.08- 7.05 (m, 2H), 3.84 and 3.83 (two s, 3H), 2.77 and 2.50 (two s, 3H) 369 (m⁺), 220 (base)

TABLE 180 Thio- amide Aldehyde Ring- com- com- forming Mass, pound poundcomponent Example ¹H-NMR m/z 2- Meth- oxy- thio- benz- amide 3-Fluoro-4- methoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.77 (br s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.07 (s, 1H),7.75-7.68 (m, 2H), 7.56-7.51 (m, 2H), 7.33-7.27 (m, 2H), 7.17- 7.13 (m,1H), 4.09 (s, 3H), 3.92 (s, 3H), 2.79 (s, 3H) 399 (m⁺), 232 (base) 2-Meth- oxy- thio- benz- amide Benz- aldehyde —

(DMSO-d₆) δ: 11.67 (br s, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.07 (s, 1H),7.79 (d, J = 7.7 Hz, 2H), 7.53 (ddd, J = 1.5, 6.9, 8.5 Hz, 1H),7.49-7.47 (m, 2H), 7.44- 7.40 (m, 2H), 7.37-7.35 (m, 1H), 7.33-7.29 (m,1H), 7.16-7.12 (m, 3H), 5.20 (s, 2H), 4.07 (s, 3H), 2.78 (s, 3H) 457(m⁺), 232 (base) 2- Meth- oxy- thio- benz- amide 4- (Methyl- thio) benz-aldehyde —

(DMSO-d₆) δ: 11.76 (br s, 1H), 8.38 (d, J = 7.7 Hz, 1H), 8.09 (s, 1H),7.77 (d, J = 8.1 Hz, 2H), 7.56-7.52 (m, 1H), 7.39 (d, J = 8.1 Hz, 2H),7.31 (d, J = 7.7 Hz, 1H), 7.17-7.13 (m, 1H), 4.11 (s, 3H), 2.78 (s, 3H),2.54 (s, 3H) 397 (m⁺), 232 (base) 2- Fluoro- thio- benz- amide — —

(DMSO-d₆) δ: 11.73 (br s, 1H), 8.35- 8.25 (m, 1H), 8.00 (s, 1H),7.65-7.55 (m, 1H), 7.51-7.35 (m, 2H), 7.29- 7.22 (m, 1H), 7.20-7.12 (m,1H), 7.03-7.00 (m, 1H), 3.84 (s, 3H), 2.80 (s, 3H) 385 (m⁺), 220 (base)

TABLE 181 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 3-Fluoro- thio- benzamide — —

(DMSO-d₆) δ: 9.40 and 9.29 (two s, 1H), 8.51 and 8.00 (two s, 1H),7.90-7.80 (m, 1H), 7.78-7.72 (m, 1H), 7.64-7.55 (m, 1H), 7.43-7.37 (m,1H), 7.35-7.30 (m, 1H), 7.25-7.09 (m, 1H), 7.02 (d, J = 8.5 Hz, 1H),3.84 and 3.82 (two s, 3H), 2.78 and 2.61 (two s, 3H) 385 (m⁺), 220(base) 4-Fluoro- thio- benzamide — —

(DMSO-d₆) δ: 11.68 (br s, 1H), 9.38 (br s, 1H), 9.28 and 8.51 (two s,1H), 8.10-7.99 (m, 2H), 7.42-7.28 (m, 3H), 7.24-7.10 (m, 1H), 7.03-7.01(m, 1H), 3.84 and 3.82 (two s, 3H), 2.77 and 2.68 (two s, 3H) 385 (m⁺),220 (base) 4-Chloro-2- methoxy- thio- benzamide — —

(DMSO-d₆) δ: 11.61 (s, 1H), 9.17 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 7.99(s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.32 (s,1H), 7.20 (dd, J = 1.9, 8.5Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 4.13 (s,3H), 3.84 (s, 3H), 2.77 (s, 3H) 431 (M⁺),  71 (base) 4-Chloro-2-methoxy- thio- benzamide 4-Hydroxy- benz- aldehyde —

(DMSO-d₆) δ: 11.62 (s, 1H), 9.97 (s, 1H), 8.37 and 8.27 (two d, J = 8.5Hz, 1H), 8.02 (s, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.42 and 7.38 (two d, J= 1.6 Hz, 1H), 7.21 and 7.18 (two dd, J = 1.9, 8.5 Hz, 1H), 6.90 (d, J =8.1 Hz, 2H), 4.13 (s, 3H), 2.78 (s, 3H) 401 (M⁺), 266 (base)

TABLE 182 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro-2- methoxy- thiobenzamide4-Hydroxy- 3-methyl- benz- aldehyde —

(DMSO-d₆) δ: 11.59 (s, 1H), 9.87 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 8.00(s, 1H), 7.56 (br d, J = 7.0 Hz, 1H), 7.46 (br s, 1H), 7.43 (d, J = 1.5Hz, 1H), 7.21 (dd, J = 1.9, 8.5 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 4.11(s, 3H), 2.77 (s, 3H), 2.17 (s, 3H) 415 (M⁺), 266 (base) 4-Chloro-2-methoxy- thiobenzamide 3,4- Dihydroxy- benz- aldehyde —

(DMSO-d₆) δ: 11.55 (s, 1H), 9.59 (s, 1H), 9.07 (s, 1H), 8.36 (d, J = 8.5Hz, 1H), 7.95 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.24 (d, J = 1.9 Hz,1H), 7.20 (dd, J = 1.9, 8.5 Hz, 1H), 7.09 (br d, J = 7.7 Hz, 1H), 6.85(d, J = 7.7 Hz, 1H), 4.13 (s, 3H), 2.78 (s, 3H) 417 (M⁺),  71 (base)4-Chloro-2- methoxy- thiobenzamide 3,4- Dimethoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.57 (s, 1H), 8.77 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.97(s, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.36 (br s, 2H), 7.21 (dd, J = 1.9,8.5 Hz, 1H), 4.06 (s, 3H), 2.76 (s, 3H), 2.22 (s, 6H) 429 (M⁺), 266(base) 4-Chloro-2- methoxy- thiobenzamide 4-Methoxy- benz- aldehyde —

(DMSO-d₆) δ: 11.69 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.07 (s, 1H), 7.78(d, J = 7.7 Hz, 2H), 7.41 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 1.9, 8.5Hz, 1H), 7.08 (d, J = 7.4 Hz, 2H), 4.13 (s, 3H), 3.83 (s, 3H), 2.78 (s,3H) 415 (M⁺), 266 (base)

TABLE 183 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro-2- methoxy- thiobenzamide3-Methoxy- benzaldehyde —

(DMSO-d₆) δ: 11.83 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.09 (s, 1H), 7.43(br s, 2H), 7.41 (d, J = 1.9 Hz, 1H), 7.36 (br s, 1H), 7.21 (dd, J =1.9, 8.5 Hz, 1H), 7.06 (d, J = 7.0 Hz, 1H), 4.11 (s, 3H), 3.81 (s, 3H),2.77 (s, 3H) 415 (M⁺), 266 (base) 4-Chloro-2- methoxy- thiobenzamide4-Hydroxy- 3-methoxy- benzaldehyde —

(DMSO-d₆) δ: 11.69 (s, 1H), 9.56 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.01(s, 1H), 7.42 (d, J = 1.5 Hz, 1H), 7.32 (br s, 2H), 7.21 (dd, J = 1.9,8.5 Hz, 1H), 6.91 (d, J = 7.4 Hz, 1H), 4.07 (s, 3H), 3.80 (s, 3H), 2.77(s, 3H) 431 (M⁺), 266 (base) 4-Chloro-2- methoxy- thiobenzamide4-Methoxy-3- methyl- benzaldehyde —

(DMSO-d₆) δ: 11.66 (s, 1H), 8.36 (d, J = 8.1 Hz, 1H), 8.04 (s, 1H), 7.66(br d, J = 7.7 Hz, 1H), 7.57 (br s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.21(dd, J = 1.9, 8.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 4.10 (s, 3H), 3.86(s, 3H), 2.77 (s, 3H), 2.21 (s, 3H) 429 (M⁺), 266 (base) 4-Chloro-2-methoxy- thiobenzamide 2,3-Dihydro- benzofuran-5- carbaldehyde —

(DMSO-d₆) δ: 11.62 (s, 1H), 8.36 (d, J = 8.5 Hz, 1H), 8.06 (s, 1H), 7.68(s, 1H), 7.57 (br d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.5 Hz, 1H), 7.21(dd, J = 1.9, 8.5 Hz, 1H), 6.90 (d, J = 8.5 Hz, 1H), 4.62 (t, J = 8.5Hz, 2H), 4.12 (s, 3H), 3.26 (t, J = 8.5 Hz, 2H), 2.78 (s, 3H) 427 (M⁺),266 (base)

TABLE 184 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro-2- methoxy- thiobenzamide4-Hydroxy- 3,5-dimethyl- benzaldehyde —

(DMSO-d₆) δ: 11.58 (s, 1H), 8.78 (s, 1H), 8.35 (d, J = 7.7 Hz, 1H), 7.98(s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.36 (br s, 2H), 7.21 (dd, J = 1.9,8.5 Hz, 1H), 4.07 (s, 3H), 2.77 (s, 3H), 2.22 (s, 6H) 429 (M⁺), 266(base) 4-Chloro-2- methoxy- thiobenzamide 6-Methoxy- 3-pyridine-carbaldehyde —

(DMSO-d₆) δ: 11.86 (s, 1H), 8.61 (s, 1H), 8.37 (d, J = 8.8 Hz, 1H), 8.18(d, J = 9.3 Hz, 1H), 8.11 (s, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.21 (dd, J= 1.9, 8.8 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 4.16 (s, 3H), 3.93 (s,3H), 2.78 (s, 3H) 416 (M⁺), 266 (base) 2-Methoxy- thiobenzamide2-Hydroxy- 4-methoxy- benzaldehyde —

(DMSO-d₆) δ: 11.87 and 11.58 (two br s, 1H), 11.52 and 10.16 (two br s,1H), 8.54 and 8.36 (two br s, 2H), 7.88- 7.42 (m, 1H), 7.52 (d, J = 6.9Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.16-7.13 (m, 1H), 6.56 (br s, 1H),6.50 (s, 1H), 4.09 (s, 3H), 3.78 (s, 3H), 2.77 and 2.69 (two s, 3H) 397(m⁺), 232 (base) 2-Methoxy- thiobenzamide 4-Formyl- benzoic acid —

(DMSO-d₆) δ: 13.10 (br s, 1H), 11.94 (br s, 1H), 8.38 (d, J = 8.1 Hz,1H), 8.21 (s, 2H), 8.00- 7.85 (m, 2H), 7.57- 7.54 (m, 1H), 7.32 (d, J =8.1 Hz, 1H), 7.17- 7.14 (m, 1H), 4.12 (s, 3H), 2.79 (s, 3H) 395 (m⁺),232 (base)

TABLE 185 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Methoxy- thiobenzamide 4- Dimethyl-amino- benz- aldehyde —

(DMSO-d₆) δ: 11.51 (br s, 1H), 8.38 (d, J = 6.9 Hz, 1H), 7.99 (s, 1H),7.66 (d, J = 7.7 Hz, 2H), 7.55-7.51 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H),7.16-7.13 (m, 1H), 6.81 (d, J = 8.5 Hz, 2H), 4.13 (s, 3H), 3.00 (s, 6H),2.79 and 2.68 (two s, 3H) 394 (m⁺), 232 (base) 2-Methoxy- thiobenzamide4-(4- Morpho- linyl) benz- aldehyde —

(DMSO-d₆) δ: 11.59 (br s, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.02 (s, 1H),7.71 (d, J = 8.1 Hz, 2H), 7.56-7.51 (m, 1H), 7.30 (d, J = 8.1 Hz, 1H),7.17-7.13 (m, 1H), 7.05 (d, J = 8.1 Hz, 2H), 4.12 (s, 3H), 3.76 (t, J =5.0 Hz, 4H), 3.24 (t, J = 5.0 Hz, 4H), 2.79 and 2.68 (two s, 3H) 436(m⁺), 232 (base) 2-Methoxy- thiobenzamide 1H- Indole- 5-carb- aldehyde —

(DMSO-d₆) δ: 11.60 (br s, 1H), 11.34 (br s, 1H), 8.42-8.35 (m, 1H), 8.21(s, 1H), 7.92 (s, 1H), 7.80-7.70 (m, 1H), 7.60-7.50 (m, 2H), 7.43 (s,1H), 7.33 (d, J = 8.5 Hz, 1H), 7.16 (t, J = 7.3 Hz, 1H), 6.54 (s, 1H),4.16 (s, 3H), 2.80 (s, 3H) 390 (m⁺), 232 (base) 2-Methoxy- thiobenzamide1H- Indole- 6-carb- aldehyde —

(DMSO-d₆) δ: 11.63 (br s, 1H), 11.33 (br s, 1H), 8.39 (d, J = 7.3 Hz,1H), 8.21 (s, 1H), 7.71-7.68 (m, 3H), 7.56-7.52 (m, 1H), 7.48-7.47 (m,1H), 7.32 (d, J = 8.5 Hz, 1H), 7.17-7.13 (m, 1H), 6.51 (s, 1H), 4.12 (s,3H), 2.80 (s, 3H) 390 (m⁺), 232 (base)

TABLE 186 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Methoxy- thiobenzamide 1-Methyl-1H-indole-5- carbaldehyde —

(DMSO-d₆) δ: 11.61 (br s, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.21 (s, 1H),7.92 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.55(t, J = 6.9 Hz, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.33 (d, J = 8.5 Hz, 1H),7.16 (t, J = 7.3 Hz, 1H), 6.53 (d, J = 3.1 Hz, 1H), 4.16 (s, 3H), 3.85(s, 3H), 2.80 and 2.68 (two s, 3H) 404 (m⁺), 232 (base) 2-Methoxy-thiobenzamide 1-Methyl-1H- indole-6- carbaldehyde —

(DMSO-d₆) δ: 11.73 (br s, 1H), 8.39 (d, J = 7.7 Hz, 1H), 8.24 (s, 1H),7.84 (d, J = 6.6 Hz, 1H), 7.71 (br s, 2H), 7.56-7.52 (m, 1H), 7.46 (d, J= 3.1 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 7.17- 7.14 (m, 1H), 6.51 (d, J= 2.7 Hz, 1H), 4.13 (s, 3H), 3.85 (s, 3H), 2.80 (s, 3H) 404 (m⁺), 232(base) 4-Chloro-2- methoxy- thiobenzamide 1H-Indole-4- carbaldehyde —

(DMSO-d₆) δ: 11.68 (br s, 1H), 9.49 (s, 1H), 8.28 (s, 1H), 8.26 (s, 1H),7.53 (d, J = 8.1 Hz, 1H), 7.50-7.49 (m, 1H), 7.41-7.38 (m, 2H),7.23-7.17 (m, 3H), 4.07 (s, 3H), 3.85 (s, 3H), 2.60 (s, 3H) 424 (m⁺),266 (base) 4-Chloro-2- methoxy- thiobenzamide 1-Methyl-1H- indole-4-carbaldehyde —

(DMSO-d₆) δ: 11.70 (br s, 1H), 8.37 (d, J = 7.7 Hz, 1H), 7.59- 7.57 (m,2H), 7.48 (d, J = 3.1 Hz, 1H), 7.41-7.37 (m, 1H), 7.29 (br s, 1H), 7.22(dd, J = 1.9, 8.5 Hz, 1H), 7.18 (dd, J = 1.9, 8.5 Hz, 1H), 6.86 (br s,1H), 4.06 (s, 3H), 3.85 (s, 3H), 2.76 (s, 3H) 438 (m⁺), 266 (base)

TABLE 187 Ring- Thio- form- amide ing com- Aldehyde com- Mass, poundcompound ponent Example ¹H-NMR m/z 4- Chloro- 2-meth- oxy thio- benz-amide 1-Methyl- 1H-indole- 7-carb- aldehyde —

(DMSO-d₆) δ: 8.43-8.35 (m, 1H), 8.00-7.92 (m, 1H), 7.73-7.67 (m, 1H),7.41 (s, 1H), 7.35 (d, J = 3.1 Hz, 1H), 7.23-7.17 (m, 3H), 6.51 (d, J =3.1 Hz, 1H), 4.11 (s, 3H), 4.04 (s, 3H), 2.80 (s, 3H) 438 (m⁺), 266(base) 2-Meth- oxy thio- benz- amide Quinoline- 6-carb- aldehyde —

(DMSO-d₆) δ: 11.94 (brs, 1H), 8.95(dd, J = 1.5, 4.2 Hz, 1H), 8.46-8.43(m, 2H), 8.40 (d, J = 7.7 Hz, 1H), 8.35 (s, 1H), 8.23 (d, J = 1.5 Hz,1H), 8.15 (d, J = 8.1 Hz, 1H), 7.61 (dd, J = 4.2, 8.1 Hz, 1H), 7.57-7.53(m, 1H), 7.34 (d, J = 8.5 Hz, 1H), 7.18-7.14 (m, 1H), 4.15 (s, 3H), 2.80(s, 3H) 402 (m⁺), 232 (base) 2- Meth- oxy thio- benz- amide 4-Methyl-3,4- dihydro- 2H-1,4- benzoxa- zine-7- carb- aldehyde —

(DMSO-d₆) δ: 11.51 (brs, 1H), 8.38 (d, J = 7.3 Hz, 1H), 7.94 (s, 1H),7.52 (dt, J = 1.5, 8.5 Hz, 1H), 7.31-7.29 (m, 2H), 7.16-7.12 (m, 1H),6.74 (d, J = 8.5 Hz, 1H), 4.26-4.24 (m, 2H), 4.13 (s, 3H), 3.35 (t, J =4.2 Hz, 2H), 2.93 (s, 3H), 2.78 (s, 3H) 422 (m⁺), 232, 174 (base) 2-Meth- oxy thio- benz- amide Coumarin- 6-carb- aldehyde —

(DMSO-d₆) δ: 11.87 (brs, 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.32 (d, J = 1.9Hz, 1H), 8.21 (d, J = 9.6 Hz, 1H), 8.12 (dd, J = 1.5, 8.5 Hz, 1H), 8.02(s, 1H), 7.60 (d, J = 8.9 Hz, 1H), 7.56-7.52 (m, 1H), 7.31 (d, J = 8.1Hz, 1H), 7.17-7.13 (m, 1H), 6.57 (d, J = 9.6 Hz, 1H), 4.07 (s, 3H), 2.78(s, 3H) 419 (m⁺), 232 (base)

TABLE 108 Thio- Alde- Ring- amide hyde forming com- com- com- Mass,pound pound ponent Example ¹H-NMR m/z 4-Chloro thio- benzamide — Ethyl2- chloro-3- oxo- penta- noate

(DMSO-d₆) δ: 11.69 (s, 1H), 9.36 (s, 1H), 8.30-7.90 (m, 3H), 7.62 (dt, J= 1.6 Hz, J = 2.3 Hz, J = 8.5 Hz, 2H), 7.27 (d, J = 1.9 Hz, 1H), 7.10(d, J = 8.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.28-3.16(m, 2H), 1.29 (t, J = 7.3 Hz, 3H) 415 (M⁺), 250 (base) 4-Chloro thio-benzamide — Methyl 2- chloro- 3- cyclo- propyl- 3-oxo pro- pionate

(DMSO-d₆) δ: 11.70 (s, 1H), 9.35 (s, 1H), 8.31-7.82 (m, 3H), 7.60 (dt, J= 1.9 Hz, J = 2.3 Hz, J = 8.9 Hz, 2H), 7.27 (d, J = 2.0 Hz, 1H), 7.10(d, J = 7.7 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H), 3.30-3.20(m, 1H), 1.20-0.98 (m, 4H) 427 (M⁺), 97 (base) 4-Chloro thio- benzamide— Ethyl 2- chloro- 3-oxo- hexa- noate

(DMSO-d₆) δ: 11.66 (s, 1H), 9.36 (s, 1H), 8.30-7.90 (m, 3H), 7.61 (dt, J= 1.9 Hz, J = 8.5 Hz, 2H), 7.26 (d, J = 1.9 Hz, 1H), 7.09 (d, J = 8.1Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 3.82 (s, 3H), 3.27-2.96 (m, 2H), 1.76(sextet, J = 7.3 Hz, J = 7.7 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H) 429 (M⁺),65 (base)

TABLE 189 Ring- Thio- Alde- form- amide hyde ing com- com- com- Mass,pound pound ponent Example ¹H-NMR m/z 4- Methoxy thiobenz- amide — —

(DMSO-d₆) δ: 11.60 (s, 1H), 9.36 (br, 1H), 8.32-7.78 (m, 3H), 7.28 (s,1H), 7.10 (d, J = 8.9 Hz, 2H + 1H), 7.01 (d, J = 8.1 Hz, 1H), 3.85 (s,3H), 3.82 (s, 3H), 2.74 (s, 3H) 397 (M⁺), 232 (base) 4- Methoxythiobenz- amide 4-Hy- droxy- 3,5- di- methyl benz- aldehyde —

(DMSO-d₆) δ: 11.59 (s, 1H), 8.77 (s, 1H), 7.95 (d, J = 7.7 Hz, 3H), 7.37(br, 2H), 7.10 (d, J = 8.5 Hz, 2H), 3.85 (s, 3H), 2.75 (s, 3H), 2.23 (s,6H) 395 (M⁺), 232 (base) 4- Chloro thio- benz- amide 4- Hexyl- oxy-3-hydroxy benz- alde- hyde —

(DMSO-d₆) δ: 11.69 (s, 1H), 9.25 (s, 1H), 8.05 (d, J = 8.1 Hz, 2H), 7.98(s, 1H), 7.61 (dt, J = 1.9, 2.3, 8.8 Hz, 2H), 7.28 (d, J = 2.0 Hz, 1H),7.08 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 4.00 (t, J = 6.6 Hz,2H), 2.77 (s, 3H), 1.73 (quintet, J = 6.6, 7.0, 7.7 Hz, 2H), 1.44(quintet, J = 7.0, 7.3, 7.7 Hz, 2H), 1.38-1.25 (m, 4H), 0.92-0.84 (m,3H) 471 (M⁺), 71 (base)

TABLE 190 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde Ethyl 2- chloro-3- oxopentanoate Example23-106  

(DMSO-d₆) δ: 11.68 (s, 1H), 8.78 (s, 1H), 8.02 (d, J = 8.1 Hz, 2H), 7.97(s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.35 (s, 1H), 3.27-3.17 (m, 2H), 2.22(s, 6H), 1.28 (t, J = 7.3 Hz, 3H) 431 (M⁺), 250 (base) 4-Chlorothiobenzamide 4-Hydroxy- 3,5-dimethyl benzaldehyde Ethyl 2- chloro-3-oxopentanoate Example 23-107  

(DMSO-d₆) δ: 11.65 (s, 1H), 8.77 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.97(s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.35 (s, 2H), 3.25-3.15 (m, 2H), 2.22(s, 6H), 1.75 (sextet, J = 7.3 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H) 427(M⁺), 264 (base) 4-Chloro thiobenzamide 4-Hydroxy- 3-methyl benzaldehydeEthyl 2- chloro-3- oxopentanoate Example 23-108  

(DMSO-d₆) δ: 11.66 (s, 1H), 9.78 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.99(s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.50 (s, 1H), 7.42 (d, J = 7.3 Hz,1H), 6.88 (d, J = 8.1 Hz, 1H), 3.27- 3.17 (m, 2H), 2.18 (s, 3H), 1.28(t, J = 7.3 Hz, 3H) 399 (M⁺), 250 (base)

TABLE 191 Ring- forming Thioamide Aldehyde com- compound compound ponentExample ¹H-NMR Mass, m/z 4-Chloro thiobenzamide 4-Hydroxy- 3,5-dimethoxybenzaldehyde — Example 23-109  

(DMSO-d₆) δ: 11.83 (s, 1H), 8.93 (s, 1H), 7.99 (dt, J = 1.9, 2.0, 2.3,2.7, 8.5 Hz, 2H + 1), 7.61 (dt, J = 1.9, 2.7, 8.5 Hz, 2H), 7.09 (s, 2H),3.85 (s, 6H), 2.79 (s, 3H) 431 (M⁺),  71 (base) 4-Chloro thiobenzamide4-Hydroxy-1- naphthaldehyde — Example 23-110  

(DMSO-d₆) δ: 11.70 (s, 1H), 10.82 (s, 1H), 8.76 (s, 1H), 8.52 (d, J =7.7 Hz, 1H), 8.25 (dd, J = 0.8, 8.1 Hz, 1H), 8.02 (d, J = 8.5 Hz, 2H),7.93-7.52 (m, 3H), 7.61 (dt, J = 1.9, 2.0, 2.7, 8.5 Hz, 2H), 7.03 (d, J= 7.0 Hz, 1H), 2.78 (s, 3H) 421 (M⁺),  71 base 4-Chloro thiobenzamide4-Hydroxy- 3-methoxy benzaldehyde — Example 23-111  

(DMSO-d₆) δ: 11.74 (s, 1H), 9.59 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H + 1H),7.61 (dt, J = 1.9, 2.7, 8.5 Hz, 4H), 7.45 (s, 1H), 7.10 (dd, J = 1.9,8.1 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 3.88 (s, 3H), 2.78 (s, 3H) 401(M⁺),  71 base

TABLE 192 Ring- forming Thioamide Aldehyde com- compound compound ponentExample ¹H-NMR Mass, m/z 4-Methoxy thiobenzamide 4-Hydroxy-3,5-dimethoxy benzaldehyde — Example 23-122  

(DMSO-d₆) δ: 11.74 (s, 1H), 8.91 (s, 1H), 7.99 (s, 1H), 7.92 (dt, J =2.7, 8.9 Hz, 2H), 7.09 (s, 2H), 7.08 (d, J = 8.5 Hz, 2H), 3.86 (s, 3H),3.85 (s, 6H), 2.77 (s, 3H) 427 (M⁺), 232 (base) 4-Methoxy thiobenzamide4-Hydroxy-1- naphthaldehyde — Example 23-123  

(DMSO-d₆) δ: 11.61 (s, 1H), 10.80 (s, 1H), 8.74 (s, 1H), 8.56 (t, J =3.5 Hz, 1H), 8.25 (d, J = 8.9 Hz, 1H), 7.95 (d, J = 8.5 Hz, 2H),7.87-7.75 (m, 1H), 7.62 (s, 1H), 7.55 (t, J = 6.9 Hz, 1H), 7.10 (dt, J =1.9, 2.7, 3.1, 8.8 Hz, 2H), 7.02 (d, J = 5.8 Hz, 1H), 3.85 (s, 3H), 2.75(s, 3H) 417 (M⁺), 232 (base) 4-Methoxy thiobenzamide — — Example 23-124 

(DMSO-d₆) δ: 11.65 (s, 1H), 9.57 (s, 1H), 7.99 (s, 1H), 7.93 (d, J = 8.9Hz, 2H), 7.47 (s, 1H), 7.09 (dt, J = 2.7, 3.1, 8.9 Hz, 2H + 1H), 6.86(d, J = 8.1 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 2.76 (s, 3H) 397 (M⁺),232 (base)

TABLE 193 Ring- Thioamide Aldehyde forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro thiobenzamide 4-Difluoro methoxy-3-hydroxy benzaldehyde — Example 23-115  

(DMSO-d₆) δ: 11.83 (br, 1H), 10.26 (br, 1H), 8.06 (t, J = 7.3 Hz, J =7.7 Hz, 3H), 7.61 (dt, J = 1.9 Hz, J = 2.7 Hz, J = 8.5 Hz, 2H), 7.42 (d,J = 2.0 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H),7.12 (t, J = 74.8 Hz, 1H), 2.77 (s, 3H) 397 (M⁺), 232 (base) 2-Chlorothiobenzamide 4-Difluoro methoxy- 3-hydroxy benzaldehyde — Example23-116  

(DMSO-d₆) δ: 11.89 (br, 1H), 10.07 (br, 1H), 8.37-8.23 (m, 1H), 8.04 (s,1H), 7.73-7.66 (m, 1H), 7.59-7.51 (m, 2H), 7.36 (s, 1H), 7.24 (d, J =8.5 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.12 (t, J = 74.8 Hz, 1H), 2.80(s, 3H) 437 (M⁺),  71 (base) 2,3-Dimethyl thiobenzamide 4-Difluoromethoxy- 3-hydroxy benzaldehyde — Example 23-117  

(DMSO-d₆) δ: 11.79 (br, 1H), 10.19 (br, 1H), 8.03 (s, 2H), 7.52 (d, J =7.3 Hz, 1H), 7.35 (d, J = 7.3 Hz, 2H), 7.28- 7.11 (m, 3H), 7.10 (t, J =74.8 Hz, 1H), 2.78 (s, 3H), 2.42 (s, 3H), 2.35 (s, 3H) 431 (M⁺), 230(base) 2-Trifluoro methyl thiobenzamide 4-Difluoro methoxy- 3-hydroxybenzaldehyde — Example 23-118  

(DMSO-d₆) δ: 11.87 (s, 1H), 10.16 (s, 1H), 8.04 (s, 1H), 7.97 (d, J =7.7 Hz, 1H), 7.88-7.76 (m, 3H), 7.33 (s, 1H), 7.21-7.11 (m, 2H), 7.10(t, J = 74.8 Hz, 1H), 2.78 (s, 3H) 471 (M⁺),  71 (base)

TABLE 194 Ring- Thioamide Aldehyde forming compound compound componentExample ¹H-NMR Mass, m/z 3-Methyl pyridine-2- carbothioamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-119  

(DMSO-d₆) δ: 11.66 (s, 1H), 8.76 (s, 1H), 8.51 (dd, J = 0.8, 4.6 Hz,1H), 7.95 (s, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.44 (dd, J = 4.6, 8.1 Hz,1H), 7.41 (s, 1H), 7.31 (s, 1H), 2.78 (s, 6H), 2.22 (s, 6H) 380 (M⁺),217 (base) 2-Methoxy thiobenzamide 4-Hydroxy- 3,5-dimethyl benzaldehyde— Example 23-120  

(DMSO-d₆) δ: 11.54 (s, 1H), 8.77 (s, 1H), 8.36 (d, J = 6.6 Hz, 1H), 7.98(s, 1H), 7.52 (ddd, J = 1.5, 7.3, 8.8 Hz, 1H), 7.37 (s, 2H), 7.30 (d, J= 8.1 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 4.04 (s, 3H), 2.76 (s, 3H),2.22 (s, 6H) 395 (M⁺), 232 (base) 2-Methoxy thiobenzamide 4-Hydroxy-3-methyl benzaldehyde — Example 23-121  

(DMSO-d₆) δ: 11.56 (s, 1H), 9.85 (s, 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.00(s, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.53 (ddd, J = 1.9, 7.3, 8.5 Hz, 1H),7.47 (d, J = 1.5 Hz, 1H), 7.31 (t, J = 8.5 Hz, 1H), 7.14 (td, J = 0.8,7.7 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 4.08 (s, 3H), 2.78 (s, 3H), 2.18(s, 3H) 381 (M⁺), 232 (base) 2,4-Dimethyl thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-122  

(DMSO-d₆) δ: 11.62 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.91 (d, J = 8.1Hz, 1H), 7.35 (s, 2H), 7.24 (s, 1H), 7.18 (d, J = 8.1 Hz, 1H), 2.78 (s,3H), 2.65 (s, 3H), 2.35 (s, 3H), 2.20 (s, 6H) 393 (M⁺), 230 (base)

TABLE 195 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro-2- methyl thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-123  

(DMSO-d₆) δ: 11.67 (s, 1H), 8.78 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.96(s, 1H), 7.55 (s, 1H), 7.44 (dd, J = 2.0 Hz, J = 8.5 Hz, 1H), 7.34 (s,2H), 2.79 (s, 3H), 2.69 (s, 3H), 2.20 (s, 6H) 413 (M⁺),  71 (base)2-Methyl thiobenzamide 4-Hydroxy- 3,5-dimethyl benzaldehyde Ethyl 2-chloro-3- oxopropionate Example 23-124  

(DMSO-d₆) δ: 11.86 (s, 1H), 8.81 (s, 1H), 8.70 (s, 1H), 8.02 (s, 1H),8.01 (s, 1H), 7.48-7.32 (m, 5H), 2.68 (s, 3H), 2.22 (s, 6H) 365 (M⁺),174 (base) 3-Chloro-2- methyl thiobenzamide — — Example 23-125  

(DMSO-d₆) δ: 11.72 (s, 1H), 9.27 (s, 1H), 8.00 (s, 1H), 7.71 (d, J = 7.7Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.39 (t, J = 7.3, 8.1 Hz, 1H), 7.23(s, 1H), 7.08 (dd, J = 1.9, 8.5 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 3.81(s, 3H), 2.79 (s, 3H), 2.58 (s, 3H) 415 (M⁺),  71 (base) 2,5-Dimethylthiobenzamide — — Example 23-126  

(DMSO-d₆) δ: 11.68 (s, 1H), 9.23 (s, 1H), 7.98 (s, 1H), 7.73 (s, 1H),7.33-7.26 (m, 2H), 7.24 (dd, J = 1.6, 7.7 Hz, 1H), 7.09 (dd, J = 1.2,8.1 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H), 2.78 (s, 3H), 2.57(s, 3H), 2.36 (s, 3H) 395 (M⁺), 230 (base)

TABLE 196 Ring- Thioamide Aldehyde forming compound compound componentExample ¹H-NMR Mass, m/z 2,5-Dimethyl thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-127  

(DMSO d₆) δ: 11.65 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.82 (s, 1H),7.36 (s, 2H), 7.31 (d, J = 7.7 Hz, 1H), 7.24 (dd, J = 1.6, 8.1 Hz, 1H),2.80 (s, 3H), 2.63 (s, 3H), 2.36 (s, 3H), 2.21 (s, 6H) 393 (M⁺), 230(base) Cyclohexane carbothiamide — — Example 23-128  

(DMSO-d₆) δ: 11.51 (s, 1H), 9.26 (s, 1H), 7.94 (s, 1H), 7.22 (s, 1H),7.07 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H),3.05-2.93 (m, 1H), 2.66 (s, 3H), 2.08 (s, 1H), 2.06 (s, 1H), 1.80 (dd, J= 2.7, 9.6 Hz, 1H), 1.70 (d, J = 12.7 Hz, 1H), 1.64-1.34 (m, 4H), 1.28(d, J = 12.0, 12.3 Hz, 1H) 373 (M⁺), 208 (base) Cyclohexanecarbothiamide 4-Hydroxy- 3,5-dimethyl benzaldehyde — Example 23-129  

(DMSO-d₆) δ: 11.51 (s, 1H), 8.74 (s, 1H), 7.91 (s, 1H), 7.32 (s, 2H),3.05-2.92 (m, 1H), 2.66 (s, 3H), 2.20 (s, 6H), 2.11 (d, J = 8.9 Hz, 2H),1.79 (dt, J = 2.7, 3.1, 3.5, 12.7 Hz, 2H), 1.69 (d, J = 12.4 Hz, 1H),1.61-1.19 (m, 5H) 371 (M⁺), 156 (base) 3-Methoxy-2- methyl thiobenzamide— — Example 23-130  

(DMSO-d₆) δ: 11.67 (s, 1H), 9.24 (s, 1H), 7.98 (s, 1H), 7.39- 7.28 (m,2H), 7.23 (s, 1H), 7.15 (d, J = 9.3 Hz, 1H), 7.08 (dd, J = 1.5, 8.5 Hz,1H), 6.99 (d, J = 8.1 Hz, 1H), 3.87 (s, 3H), 3.81 (s, 3H), 2.78 (s, 3H),2.40 (s, 3H) 411 (M⁺), 246 (base)

TABLE 197 Ring- forming Thioamide Aldehyde com- compound compound ponentExample ¹H-NMR Mass, m/z 3-Methoxy-2- methyl thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-131  

(DMSO-d₆) δ: 11.65 (s, 1H), 8.77 (s, 1H), 7.96 (s, 1H), 7.43 (d, J = 7.3Hz, 1H), 7.37-7.29 (m, 3H), 7.15 (d, J = 8.9 Hz, 1H), 3.87 (s, 3H), 2.79(s, 3H), 2.46 (s, 3H), 2.19 (s, 6H) 409 (M⁺),  71 (base) Thioacetamide —— Example 23-132  

(DMSO-d₆) δ: 11.53 (br s, 1H), 9.33 (s, 1H), 7.93 (br s, 1H), 7.26 (s,1H), 7.06 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 3.81 (s, 3H),2.67 (s, 3H), 2.66 (s, 3H) 305 (M⁺), 140 (base) Thioacetamide 4-Hydroxy-3,5-dimethyl benzaldehyde — Example 23-133  

(DMSO-d₆) δ: 11.49 (br s, 1H), 8.75 (s, 1H), 7.92 (br s, 1H), 7.30 (s,2H), 2.66 (s, 6H), 2.21 (s, 6H) 303 (M⁺), 140 (base) 2,4-Dimethylthiazole-5- carbothioamide — — Example 23-134  

(DMSO-d₆) δ: 11.73 (s, 1H), 9.18 (s, 1H), 7.98 (s, 1H), 7.31 (s, 1H),7.12 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H), 2.73(s, 3H), 2.69 (s, 3H), 2.67 (s, 3H) 402 (M⁺),  71 (base)

TABLE 198 Ring- Thioamide Aldehyde forming compound compound componentExample ¹H-NMR Mass, m/z 4-Methyl pyridine-3- carbothioamide — — Example23-135  

(DMSO-d₆) δ: 11.74 (s, 1H), 9.29 (s, 1H), 9.00 (s, 1H), 8.56 (d, J = 5.0Hz, 1H), 7.99 (s, 1H), 7.46 (d, J = 5.0 Hz, 1H), 7.28 (d, J = 2.0 Hz,1H), 7.09 (dd, J = 1.6, 8.5 Hz, 1H), 6.99 (d, J = 8.1 Hz, 1H), 3.81 (s,3H), 2.81 (s, 3H), 2.64 (s, 3H) 382 (M⁺),  71 (base) 4-Methylpyridine-3- carbothioamide 4-Hydroxy- 3,5-dimethyl benzaldehyde —Example 23-136  

(DMSO-d₆) δ: 11.71 (s, 1H), 9.09 (s, 1H), 8.78 (s, 1H), 8.55 (d, J = 5.0Hz, 1H), 7.97 (s, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.35 (s, 2H), 2.82 (s,3H), 2.70 (s, 3H), 2.20 (s, 6H) 380 (M⁺),  71 (base) 4-Methylthiazole-5- carbothioamide — — Example 23-137  

(DMSO-d₆) δ: 11.76 (s, 1H), 9.19 (s, 1H), 9.15 (s, 1H), 7.98 (s, 1H),7.32 (s, 1H), 7.13 (d, J = 6.5 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.83(s, 3H), 2.78 (s, 3H), 2.76 (s, 3H) 388 (M⁺), 223 (base) 3-Chloropyridine-2- carbothioamide 4-Methoxy benzaldehyde — Example 23-138  

(DMSO-d₆) δ: 11.81 (s, 1H), 8.69 (s, 1H), 8.14 (dd, J = 1.2, 8.1 Hz,1H), 8.09 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.58 (dd, J = 4.6, 8.1 Hz,1H), 7.04 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 2.78 (s, 3H) 386 (M⁺),  71(base)

TABLE 199 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 3-Chloro pyridine-2- carbothioamide — —Example 23-139  

(DMSO-d₆) δ: 11.75 (s, 1H), 9.20 (s, 1H), 8.67 (d, J = 3.8 Hz, 1H), 8.15(dd, J = 1.6, 8.1 Hz, 1H), 8.00 (s, 1H), 7.58 (dd, J = 4.6, 8.1 Hz, 1H),7.19 (s, 1H), 7.11 (d, J = 8.1 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 3.82(s, 3H), 2.77 (s, 3H) 402 (M⁺),  71 (base) 4-Chloro thiobenzamide5-Formyl-2- methoxyphenyl boronic acid — Example 23-140  

(DMSO-d₆) δ: 11.76 (s, 1H), 8.30 (s, 1H), 8.13-8.04 (m, 2H), 8.02 (d, J= 8.5 Hz, 1H), 7.91 (s, 2H), 7.76-7.64 (m, 2H), 7.60 (dt, J = 1.9, 2.0,2.7, 8.5 Hz, 1H), 7.09 (d, J = 8.9 Hz, 1H), 3.88 (s, 3H), 2.79 (s, 3H)61 (base) 2-Methyl thiobenzamide 4-Methoxy benzaldehyde Ethyl 2-chloro-3- oxopropionate Example 23-141  

(DMSO-d₆) δ: 11.95 (s, 1H), 8.71 (s, 1H), 8.12 (s, 1H), 7.89 (d, J = 7.7Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.74-7.68 (m, 1H), 7.49-7.34 (m, 3H),7.06 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.61 (s, 3H) 351 (M⁺), 174(base) 2-Chloro thiobenzamide — Ethyl 2- chloro-3- oxopropionate Example23-142  

(DMSO-d₆) δ: 11.96 (s, 1H), 9.19 (s, 1H), 8.75 (s, 1H), 8.38- 8.32 (m,1H), 8.03 (s, 1H), 7.74-7.69 (m, 1H), 7.61-7.53 (m, 2H), 7.35 (d, J =1.9 Hz, 1H), 7.16 (dd, J = 1.9, 8.5 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H),3.84 (s, 3H) 387 (M⁺),  57 (base)

TABLE 200 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Chloro thiobenzamide 4-Hydroxy-3,5-dimethyl benzaldehyde Ethyl 2- chloro-3- oxopropionate Example23-143  

(DMSO-d₆) δ: 11.91 (s, 1H), 8.83 (s, 1H), 8.73 (s, 1H), 8.46- 8.40 (m,1H), 8.01 (s, 1H), 7.77-7.70 (m, 1H), 7.60-7.53 (m, 2H), 7.41 (s, 2H),2.23 (s, 6H) 385 (M⁺), 238 (base) 2,5-Dimethyl- 2H-pyrazole-3-carbothioamide — — Example 23-144  

(DMSO-d₆) δ: 11.58 (s, 1H), 9.23 (s, 1H), 7.97 (s, 1H), 7.18 (s, 1H),7.10 (s, 1H), 7.01 (d, J = 6.9 Hz, 1H), 6.61 (s, 1H), 3.83 (s, 3H), 3.82(s, 3H), 2.70 (s, 3H), 2.32 (s, 3H) 385 (M⁺), 220 (base) 2-Methoxythiobenzamide 4-Methoxy benzaldehyde — Example 23-145  

(DMSO-d₆) δ: 11.66 (s, 1H), 8.69 (s, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.08(s, 1H), 7.79 (d, J = 7.7 Hz, 2H), 7.53 (ddd, J = 2.0 Hz, J = 7.4 Hz, J= 8.8 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H), 7.14 (td, J = 1.2 Hz, J = 8.1Hz, 1H), 7.08 (d, J = 8.1 Hz, 1H), 4.10 (s, 3H), 3.83 (s, 3H), 2.78 (s,3H) 381 (M⁺), 232 (base) 2,5-Dimethyl- 2H-pyrazole-3- carbothioamide4-Hydroxy- 3,5-dimethyl benzaldehyde — Example 23-146  

(DMSO-d₆) δ: 11.58 (s, 1H), 8.76 (s, 1H), 7.93 (s, 1H), 7.38 (s, 2H),6.60 (d, J = 0.8 Hz, 1H), 3.81 (s, 3H), 2.72 (s, 3H), 2.32 (s, 3H), 2.23(s, 6H) 383 (M⁺), 220 (base)

TABLE 201 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Chloro thiobenzamide 4-Methoxybenzaldehyde Ethyl 2- chloro-3- oxopropionate Example 23-147  

(DMSO-d₆) δ: 12.02 (s, 1H), 8.75 (s, 1H), 8.38-8.32 (m, 1H), 8.12 (s,1H), 7.78 (d, J = 8.5 Hz, 2H), 7.75-7.65 (m, 1H), 7.61-7.53 (m, 2H),7.05 (dt, J = 1.9, 2.7, 8.9 Hz, 2H), 3.83 (s, 3H) 371 (M⁺), 238 (base)2-Chloro thiobenzamide 4-(1,3,2- Dioxaborinan- 2-yl) benzaldehyde —Example 23-148  

(DMSO-d₆) δ: 11.90 (s, 1H), 8.13 (s, 1H), 8.04 (d, J = 8.1 Hz, 2H), 7.79(d, J = 7.3 Hz, 2H), 7.73 (d, J = 7.7 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H),4.13 (t, J = 5.4 Hz, 4H), 2.77 (s, 3H), 2.03 (quintet, J = 5.4 Hz, 2H)439 (M⁺), 236 (base) 2-Propyloxy thiobenzamide 4-Methoxy benzaldehyde —Example 23-149  

(DMSO-d₆) δ: 11.64 (s, 1H), 8.36 (d, J = 7.7 Hz, 1H), 8.09 (br, 1H),7.70 (d, J = 8.9 Hz, 2H), 7.49 (ddd, J = 1.9, 7.3, 8.5 Hz, 1H), 7.27 (d,J = 8.1 Hz, 1H), 7.14-7.08 (m, 1H), 7.03 (dt, J = 2.0, 2.7, 3.1, 8.5 Hz,2H), 4.26 (t, J = 6.6 Hz, 2H), 3.82 (s, 3H), 2.75 (s, 3H), 1.79 (br,2H), 0.87 (br, 3H) 409 (M⁺), 260 (base) 3-Methyl pyridine-2-carbothioamide 4-Methoxy benzaldehyde — Example 23-150  

(DMSO-d₆) δ: 11.74 (s, 1H), 8.54 (s, 1H), 8.08 (s, 1H), 7.83 (d, J = 7.7Hz, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.44 (dd, J = 4.6, 7.7 Hz, 1H), 7.04(d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 2.77 (s, 3H) 366 (M⁺), 217 (base)

TABLE 202 Ring- Thioamide Aldehyde forming compound compound componentExample ¹H-NMR Mass, m/z 2-Chloro thiobenzamide 3-Formyl- phenylboronicacid — Example 23-151  

(DMSO-d₆) δ: 11.87 (s, 1H), 8.41 (s, 1H), 8.25 (s, 1H), 8.25- 7.98 (m,4H), 7.90 (d, J = 7.3 Hz, 1H), 7.78-7.57 (m, 3H), 7.47 (t, J = 7.3 Hz,1H), 2.80 (s, 2H) 59 (base) 2-Chloro thiobenzamide 2,3-Dihydrobenzofuran-5- carbaldehyde — Example 23-152  

(DMSO-d₆) δ: 11.71 (s, 1H), 8.05 (s, 1H), 8.03 (d, J = 8.1 Hz, 2H), 7.67(s, 1H), 7.61 (d, J = 8.5 Hz, 2H), 7.50 (d, J = 7.3 Hz, 1H), 6.88 (d, J= 7.7 Hz, 1H), 4.61 (t, J = 8.9 Hz, 2H), 3.26 (t, J = 8.5 Hz, 2H), 2.77(s, 3H) 397 (M⁺),  71 (base) 2-Methoxy thiobenzamide 2,3-Dihydrobenzofuran-5- carbaldehyde — Example 23-153  

(DMSO-d₆) δ: 11.59 (s, 1H), 8.37 (d, J = 7.3 Hz, 1H), 8.06 (s, 1H), 7.70(s, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.53 (td, J = 1.6, 8.9 Hz, 1H), 7.30(d, J = 8.5 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H), 6.90 (t, J = 8.1 Hz, 1H),4.61 (t, J = 8.8, 8.9 Hz, 2H), 4.09 (s, 3H), 3.26 (t, J = 8.5, 8.9 Hz,2H), 2.78 (s, 3H) 393 (M⁺), 232 (base)

TABLE 203 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2,3-Dihydro benzo[1,4] dioxin-5-carbothioamide — — Example 23-154  

(DMSO-d₆) δ: 11.63 (s, 1H), 9.15 (br, 1H), 7.98 (s, 1H), 7.89 (d, J =7.0 Hz, 1H), 7.36 (d, J = 7.0 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H),7.05-7.00 (m, 1H), 7.03 (dd, J = 1.9, 7.7 Hz, 1H), 6.99 (d, J = 7.7, 7.7Hz, 1H), 4.60 (br, 2H), 4.44-4.34 (m, 2H), 3.84 (s, 3H), 2.78 (s, 3H)425 (M⁺), 260 (base) 2,3-Dihydro benzo[1,4] dioxin-5- carbothioamide4-Methoxy benzaldehyde — Example 23-155  

(DMSO-d₆) δ: 11.68 (s, 1H), 8.07 (s, 1H), 7.90 (d, J = 6.9 Hz, 1H), 7.77(d, J = 7.7 Hz, 2H), 7.09 (d, J = 8.1 Hz, 1H), 7.08-7.02 (m, 1H), 7.03(dd, J = 1.9, 8.1 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 4.58 (s, 2H), 4.42(s, 2H), 3.83 (s, 3H), 2.78 (s, 3H) 409 (M⁺), 260 (base) 2-Chlorothiobenzamide 4-Methoxy benzaldehyde Ethyl 2- chloro-3- oxopropionateExample 23-156  

(DMSO-d₆) δ: 11.96 (s, 1H), 8.68 (s, 1H), 8.12 (s, 1H), 8.09 (d, J = 8.5Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.10 (d, J= 8.9 Hz, 2H), 3.84 (s, 3H) 371 (M⁺), 238 (base)

TABLE 204 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 2-Methoxy thiobenzamide 4-Methoxybenzaldehyde Ethyl 2- chloro-3- oxopropionate Example 23-157  

(DMSO-d₆) δ: 11.81 (s, 1H), 8.69 (s, 1H), 8.14 (dd, J = 1.2, 8.1 Hz,1H), 8.09 (s, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.58 (dd, J = 4.6, 8.1 Hz,1H), 7.04 (d, J = 8.9 Hz, 2H), 3.82 (s, 3H), 2.78 (s, 3H) 367 (M⁺), 218(base) 4-Chloro-2- methoxy thiobenzamide 4-Methoxy benzaldehyde Ethyl 2-chloro-3- oxopropionate Example 23-158  

(DMSO-d₆) δ: 11.90 (s, 1H), 8.68 (s, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.11(s, 1H), 7.81 (d, J = 8.1 Hz, 2H), 7.44 (s, 1H), 7.23 (dd, J = 1.2, 8.5Hz, 1H), 7.10 (d, J = 8.5 Hz, 2H), 4.16 (s, 3H), 3.84 (br, 3H) 401 (M⁺),252 (base) 2-Methoxy thiobenzamide Benzofuran-5- carbaldehyde — Example23-159  

(DMSO-d₆) δ: 11.75 (s, 1H), 8.39 (d, J = 7.3 Hz, 1H), 8.24 (br, 1H),8.09 (d, J = 1.9 Hz, 1H), 8.04 (s, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.77(d, J = 8.5 Hz, 1H), 7.54 (ddd, J = 1.5, 7.3, 8.5 Hz, 1H), 7.31 (d, J =8.1 Hz, 1H), 7.15 (td, J = 1.2, 8.1 Hz, 1H), 7.06 (td, J = 0.8, 1.9 Hz,1H), 4.11 (s, 3H), 2.80 (s, 3H) 391 (M⁺), 232 (base) 2-Methoxythiobenzamide 5-Formyl-2- methoxy phenylboronic acid — Example 23-160  

(DMSO-d₆) δ: 11.62 (s, 1H), 8.36 (d, J = 6.6 Hz, 1H), 8.24- 7.76 (m,5H), 7.56- 7.49 (m, 1H), 7.30 (ddd, J = 0.8, 2.7, 8.5 Hz, 1H), 7.14 (td,J = 0.8, 7.7 Hz, 1H), 7.13-7.06 (m, 1H), 4.08 and 4.06 (two s, 3H), 3.87and 3.85 (two s, 3H), 2.77 (s, 3H) 232 (base)

TABLE 205 Thioamide Aldehyde Ring-forming Mass, compound compoundcomponent Example ¹H-NMR m/z 4-Chloro thiobenz- amide Benzofuran-5-carbaldehyde —

(DMSO-d₆) δ: 11.85 (s, 1H), 8.24 (br, 1H), 8.08 (d, J = 2.3 Hz, 1H),8.06 (d, J = 8.5 Hz, 2H), 8.02 (d, J = 1.5 Hz, 1H), 7.82 (d, J = 8.1 Hz,1H), 7.74 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.07 (s, 1H),2.78 (s, 3H) 395 (M⁺), 236 (base) 2-Methyl thiobenz- amide 4-Hydroxy-3,5-dimethyl benzaldehyde Ethyl 2- chloro-3-(4- methoxy- phenyl)-3-oxopropionate

(DMS0-d₆) δ: 11.84 and 11.77 (two s. 1H), 8.79 and 8.71 (two s, 1H),8.03-7.82 (m, 2H), 7.80 and 7.71 (two d, J = 8.1 Hz, 2H), 7.46-7.37 (m,3H), 7.29 (s, 1H), 7.12 (s, 1H), 7.04 and 6.98 (two d, J = 8.9 Hz, 2H),3.80 and 3.78 (two s, 3H), 2.69 and 2.60 (two s, 3H), 2.16 and 2.20 (twos, 6H) 471 (M⁺), 323, 308, 163 (base) 2-Methyl thiobenz- amide 4-Methoxybenzaldehyde Ethyl 2- chloro-3-(4- methoxy- phenyl)-3- oxopropionate

(DMSO-d₆) δ: 11.93 and 11.87 (two s, 1H), 8.15 and 8.02 (two s, 1H),7.79-7.89 (m, 2H), 7.71-7.66 (m, 2H), 7.51-7.38 (m, 4H), 7.06-6.97 (m,4H), 3.80 (s, 3H), 3.78 (s, 3H), 2.66 (s, 3H) 457 (M⁺), 323, 308, 163(base)

TABLE 206 Ring- forming Thioamide Aldehyde compo- Mass, compoundcompound nent Example ¹H-NMR m/z 4-Chloro- 2-methoxy thiobenz- amide4′-Methoxy acetophenone —

(DMSO-d₆) δ: 10.77 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.9Hz, 2H), 7.37 (d, J = 1.5 Hz, 1H), 7.20 (dd, J = 1.9, 8.5 Hz, 1H), 7.04(d, J = 8.9 Hz, 2H), 4.00 (s, 3H), 3.82 (s, 3H), 2.77 (s, 3H), 2.34 (s,3H) 429 (M⁺), 266 (base) 4-Chloro- 2-methoxy thiobenz- amide 5-Methoxyindan-1-one —

(DMS0-d₆) δ: 10.78 (s, 1H), 8.37 (d, J = 8.5 Hz, 1H), 7.80 (brs, 1H),7.41 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 2.0, 8.5 Hz, 1H), 7.01 (brs,2H), 4.13 (s, 3H), 3.83 (s, 3H), 3.10 (t, J = 6.2 Hz, 2H), 2.90 (t, J =6.2 Hz, 2H), 2.79 (s, 3H) 441 (M⁺), 266 (base) 4-Chloro- 2-methoxythiobenz- amide 1-Methyl-1H- benzimidazol- 5-carboxy aldehyde —

(DMSO-d₆) δ: 11.73 (brs, 1H), 8.39 (d, J = 8.9 Hz, 1H), 8.29 (s, 1H),8.25 (brs, 1H), 8.16 (brs, 1H), 7.77 (d, J = 8.9 Hz, 1H), 7.71 (d, J =8.1 Hz, 1H), 7.45 (s, 1H), 7.22 (dd, J = 1.9, J = 8.7 Hz, 1H), 4.27 (s,2H), 3.89 (s, 4H), 2.80 (s, 3H) 439 (M⁺), 266 (base)

TABLE 207 Al- Ring- de- forming hyde com- Thioamide com- po- Mass,compound pound nent Example ¹H-NMR m/z 4-Chloro- 2-methoxy thio-benzamide Exam- ple 48-2 —

(DMSO-d₆) δ: 11.73 (brs, 1H), 8.39 (d, J = 7.7 Hz, 1H), 8.24 (s, 1H),8.08 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.44(s, 1H), 7.22 (dd, J = 1.9, J = 8.5 Hz, 1H), 5.00 (s, 2H), 4.26-4.18 (m,7H), 2.80 (s, 3H) 481 (M⁺), 238 (base)

Example 23-166 5-(4-Chlorophenyl)-2-methylfuran-3-carboxylic acid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 23-1 except that methyl5-(4-chlorophenyl)-2-methylfuran-3-carboxylate was used instead of ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate.

¹H-NMR (DMSO-d₆) δ: 11.29 (s, 1H), 9.28 (s, 1H), 8.25 (s, 1H), 7.67 (d,J=8.1 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.36 (s, 1H), 7.26 (brs, 1H),7.06 (d, J=8.1 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H), 3.82 (s, 3H), 2.63 (s,3H)

Mass, m/z: 384 (M⁺), 219 (base)

Example 23-167 5-(4-Chlorophenyl)-2-methylfuran-3-carboxylic acid[1-(4-hydroxy-3,5-dimethylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 23-1 except that methyl5-(4-chlorophenyl)-2-methylfuran-3-carboxylate and4-hydroxy-3,5-dimethylbenzaldehyde were used instead of ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.26 (s, 1H), 8.71 (s, 1H), 8.22 (s, 1H), 7.68 (d,J=8.1 Hz, 2H), 7.53 (d, J=8.9 Hz, 2H), 7.36 (s, 1H), 7.30 (s, 2H), 2.62(s, 3H), 2.21 (s, 6H)

Mass, m/z: 382 (M⁺), 219 (base)

Example 23-1684-(4-Chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid(4-methoxybenzylidene)hydrazide

The title compound was obtained according to the same procedure as inExample 23-1 except that ethyl4-(4-chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate preparedin the Step 10-1-3 and 4-methoxybenzaldehyde were used instead of ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.37 (brs, 1H), 8.31 (brs, 1H), 7.65 (d, J=8.9 Hz,2H), 7.52 (s, 1H), 7.39 (s, 1H), 7.12 (d, J=1.9 Hz, 1H), 7.06 to 7.01(m, 3H), 3.91 (s, 6H), 3.82 (s, 3H)

Mass, m/z: 397 (m⁺), 248 (base)

Example 23-1694-(4-Chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid(4-hydroxy-3,5-dimethylbenzylidene)hydrazide

The title compound was obtained according to the same procedure as inExample 23-1 except that ethyl4-(4-chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate preparedin the Step 10-1-3 and 4-hydroxy-3,5-dimethylbenzaldehyde were usedinstead of ethyl 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylateand 3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.29 (brs, 1H), 8.67 (s, 1H), 8.19 (s, 1H), 7.51(d, J=2.7 Hz, 1H), 7.28 (s, 2H), 7.12 (d, J=2.3 Hz, 2H), 7.03 (dd,J=2.3, 8.5 Hz, 1H), 3.91 (s, 3H), 2.21 (s, 3H)

Mass, m/z: 411 (m⁺), 248 (base)

Example 23-1704-(4-Chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylic acid(3-hydroxy-4-methoxybenzylidene)hydrazide

The title compound was obtained according to the same procedure as inExample 23-1 except that ethyl4-(4-chloro-2-methoxyphenyl)-1-methyl-1H-pyrrole-2-carboxylate preparedin the Step 10-1-3 was used instead of ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate.

¹H-NMR (DMSO-d₆) δ: 11.31 (brs, 1H), 9.24 (s, 1H), 8.22 (s, 1H), 7.52(s, 1H), 7.37 (s, 1H), 7.24 (d, J=1.5 Hz, 1H), 7.12 (d, J=1.9 Hz, 1H),7.04 (d, J=2.3 Hz, 1H), 7.02 (d, J=1.9 Hz, 1H), 6.98 (d, J=8.5 Hz, 1H),3.91 (s, 6H), 3.81 (s, 3H)

Mass, m/z: 413 (m⁺), 248 (base)

In the formulae, Boc represents a protecting group (t-butoxycarbonylgroup), and R and R′ are the same or different and each represent anaryl group which may have a substituent (such as an alkyl group, ahydroxyl group, or an alkoxy group).

Example 24-1 Step 24-1-1 Ethyl 4-bromo-1H-pyrrole-2-carboxylate

To a solution of ethyl 1H-pyrrole-2-carboxylate (1.17 g) in carbontetrachloride (40 ml), a solution of bromine (1.48 g) in carbontetrachloride (80 ml) was added dropwise at −15° C., and the mixture wasstirred for one hour. The mixture was warmed to a room temperature, anda 2-N sodium hydroxide aqueous solution (80 ml) was added thereto. Theresulting mixture was subjected to extraction with ethyl acetate, andthe organic layer was dried over anhydrous magnesium sulfate andconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:6) to giveethyl 4-bromo-1H-pyrrole-2-carboxylate (700 mg, 38%).

¹H-NMR (CDCl₃) δ: 9.16 (brs, 1H), 6.93 (dd, J=1.5, 2.7 Hz, 1H), 6.89(dd, J=1.5, 2.7 Hz, 1H), 4.31 (q, J=6.9 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H)

Mass, m/z: 217 (M⁺), 189, 173 (base)

Step 24-1-2 4-bromopyrrole-1,2-dicarboxylic acid 1-tert-butyl ester2-ethyl ester

To a solution of ethyl 4-bromo-1H-pyrrole-2-carboxylate (700 mg)obtained in the Step 24-1-1 in acetonitrile (5 ml), di-tert-butyldicarbonate (917 mg) and 4-dimethylaminopyridine (39 mg) were added, andthe mixture was stirred for 20 hours. Ethyl ether was added thereto, andthe resulting mixture was washed with a 1 mol/L potassium bisulfateaqueous solution and a saturated sodium bicarbonate solution in order,and the organic layer was dried over anhydrous magnesium sulfate andconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=5:1) to give4-bromopyrrole-1,2-carboxylic acid 1-tert-butyl ester 2-ethyl ester (893mg, 88%).

¹H-NMR (CDCl₃) δ: 7.29 (d, J=1.9 Hz, 1H), 6.78 (d, J=1.9 Hz, 1H), 4.29(q, J=7.3 Hz, 2H), 1.57 (s, 9H), 1.34 (t, J=7.3 Hz, 3H)

Mass, m/z: 317 (M⁺), 297, 217, 57 (base)

Step 24-1-3 Ethyl 4-(2,3-dimethylphenyl)-1H-pyrrole-2-carboxylate

Dimethylformamide (3 ml) and a sodium carbonate aqueous solution (2mol/l, 0.5 ml) were added to 4-bromo-pyrrole-1,2-carboxylic acid1-tert-butyl ester 2-ethyl ester (100 mg) obtained in the Step 24-1-2,2,3-dimethylphenylboronic acid (141 mg) andtetrakis(triphenylphosphine)palladium(0) (36 mg) at 110° C. After themixture was heated and stirred for 2 hours, water was added thereto, andthe resulting mixture was subjected to extraction with ethyl acetate.The organic layer was washed with water, and then dried over anhydrousmagnesium sulfate and concentrated under a reduced pressure. The residuewas purified by silica gel thin-layer chromatography (ethylacetate:n-hexane=1:5) to give ethyl4-(2,3-dimethylphenyl)-1H-pyrrole-2-carboxylate (50 mg, 65%).

¹H-NMR (DMSO-d₆) δ: 11.98 (brs, 1H), 7.12-7.03 (m, 4H), 6.84 (dd, J=1.5,2.7 Hz, 1H), 4.26 (q, J=6.9 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H), 1.30(t, J=6.9 Hz, 3H)

Mass, m/z: 243 (M⁺) (base), 197, 129

Step 24-1-4 4-(2,3-Dimethylphenyl)-1H-pyrrole-2-carboxylic acidhydrazide

According to the same procedure as in the Step 22-1-3 except that ethyl4-(2,3-dimethylphenyl)-1H-pyrrole-2-carboxylate obtained in the Step24-1-3 was used instead of methyl5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate, the title compound (25 mg,59%) was obtained.

¹H-NMR (DMSO-d₆) δ: 11.56 (brs, 1H), 9.29 (brs, 1H), 7.09-7.03 (m, 3H),6.92 (dd, J=1.5, 2.7 Hz, 1H), 6.87 (s, 1H), 4.32 (d, J=3.9 Hz, 2H), 2.27(s, 3H), 2.24 (s, 3H)

Mass, m/z: 229 (M⁺), 198 (base)

Step 24-1-5 4-(2,3-Dimethylphenyl)-1H-pyrrole-2-carboxylic acid[1-(4-hydroxy-3,5-dimethylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that4-(2,3-dimethylphenyl)-2H-pyrazole-2-carboxylic acid hydrazide obtainedin the Step 24-1-4 and 4-hydroxy-3,5-dimethylbenzaldehyde were usedinstead of 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazideand 3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.81 (brs, 1H), 11.25 (s, 1H), 8.68 (s, 1H), 8.20(brs, 1H), 7.30 (s, 2H), 7.20-6.97 (m, 5H), 2.30 (s, 6H), 2.21 (s, 6H)

Mass, m/z: 361 (M⁺), 164 (base)

Example 24-2 4-(4-Chlorophenyl)-1H-pyrrole-2-carboxylic acid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 24-1 except that 4-chlorophenylboronic acid was used instead of2,3-dimethylphenylboronic acid in the Step 24-1-3.

¹H-NMR (DMSO-d₆) δ: 11.93 (s, 1H), 11.35 (s, 1H), 9.27 (s, 1H), 8.22 (s,1H), 7.60 (d, J=8.1 Hz, 2H), 7.49 (dd, J=1.5, 2.7 Hz, 1H), 7.40 (d,J=8.5 Hz, 2H), 7.27 (brd, J=1.2 Hz, 1H), 7.06 (dd, J=1.9, 8.5 Hz, 1H),6.99 (d, J=8.5 Hz, 1H), 3.82 (s, 3H)

Mass, m/z: 369 (M⁺), 166 (base)

Example 24-3 4-(4-Chlorophenyl)-1H-pyrrole-2-carboxylicacid[1-(4-hydroxy-3,5-dimethylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 24-1 except that 4-chlorophenylboronic acid and4-hydroxy-3,5-dimethylbenzaldehyde were used instead of2,3-dimethylphenylboronic acid and 3-hydroxy-4-methoxybenzaldehyde,respectively, in the Step 24-1-3.

¹H-NMR (DMSO-d₆) δ: 11.92 (s, 1H), 11.31 (s, 1H), 8.69 (s, 1H), 8.19 (s,1H), 7.60 (d, J=8.5 Hz, 2H), 7.49 (s, 1H), 7.40 (d, J=8.9 Hz, 2H), 7.31(s, 3H), 2.22 (s, 6H)

Mass, m/z: 367 (M⁺), 164 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, a hydroxyl group, or an alkoxy group), and R′ represents ahydrogen atom or an alkyl group.

Example 25-1 Step 25-1-1 2-(4-Chlorophenyl)-1H-imidazole-4-carboxylicacid hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-3 except that methyl2-(4-chlorophenyl)-1H-imidazole-4-carboxylate was used instead of methyl5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate.

¹H-NMR (CDCl₃) δ: 7.75 (d, J=8.9 Hz, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.01(s, 1H), 4.03 (brs, 2H)

Mass, m/z: 236 (M⁺), 205 (base)

Step 25-1-2 2-(4-Chlorophenyl)-3H-imidazole-4-carboxylicacid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that 2-(4-chlorophenyl)-1H-imidazole-4-carboxylicacid hydrazide prepared in the Step 25-1-1 was used instead of5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide.

¹H-NMR (CDCl₃) δ: 13.18 (brs, 1H), 11.18 (s, 1H), 9.26 (s, 1H), 8.40 (s,1H), 8.06 (d, J=8.5 Hz, 2H), 7.95 (s, 1H), 7.59 (d, J=8.9 Hz, 2H), 7.26(s, 1H), 7.04 (dd, J=1.9, 8.5 Hz, 1H), 6.98 (d, J=8.9 Hz, 1H), 3.81 (s,3H)

Mass, m/z: 370 (M⁺), 166 (base)

Example 25-2 2-(2-Methylphenyl)-3H-imidazole-4-carboxylicacid[1-(4-hydroxy-3,5-dimethylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 25-1 except that methyl2-(2-methylphenyl)-1H-imidazole-4-carboxylate and4-hydroxy-3,5-dimethylbenzaldehyde were used instead of methyl2-(4-chlorophenyl)-1H-imidazole-4-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CDCl₃) δ: 12.76 (brs, 1H), 11.05 (s, 1H), 8.66 (s, 1H), 8.34 (s,1H), 7.90 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.35-7.27 (m, 5H), 2.50 (s,6H), 2.21 (s, 3H)

Mass, m/z: 348 (M⁺), 164 (base)

Example 25-3 2-(2-Methylphenyl)-3H-imidazole-4-carboxylicacid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 25-1 except that methyl2-(2-methylphenyl)-1H-imidazole-4-carboxylate was used instead of methyl2-(4-chlorophenyl)-1H-imidazole-4-carboxylate.

¹H-NMR (CDCl₃) δ: 12.78 (brs, 1H), 11.09 (s, 1H), 9.25 (s, 1H), 8.38 (s,1H), 7.91 (s, 1H), 7.59 (d, J=6.9 Hz, 1H), 7.35-7.25 (m, 4H), 7.03-6.96(m, 2H), 3.81 (s, 3H), 2.53 (s, 3H)

Mass, m/z: 350 (M⁺), 164 (base)

Example 25-4 2-(2-Methylphenyl)-3H-imidazole-4-carboxylicacid[1-(4-hydroxy-3-methylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 25-1 except that methyl2-(2-methylphenyl)-1H-imidazole-4-carboxylate and4-hydroxy-3-methylbenzaldehyde were used instead of methyl2-(4-chlorophenyl)-1H-imidazole-4-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CDCl₃) δ: 12.76 (brs, 1H), 11.04 (s, 1H), 9.75 (s, 1H), 8.37 (s,1H), 7.90 (s, 1H), 7.59 (d, J=7.3 Hz, 1H), 7.44 (s, 1H), 7.35-7.30 (m,3H), 6.84 (d, J=8.1 Hz, 1H), 2.53 (s, 3H), 2.16 (s, 3H)

Mass, m/z: 334 (M⁺), 185 (base)

Example 25-5 2-(4-Chlorophenyl)-3H-imidazole-4-carboxylicacid[1-(3-hydroxy-4-methoxyphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 25-1 except that methyl2-(4-chlorophenyl)-5-methyl-1H-imidazole-4-carboxylate was used insteadof methyl 2-(4-chlorophenyl)-1H-imidazole-4-carboxylate.

¹H-NMR (CDCl₃) δ: 12.88 (brs, 1H), 11.03 (s, 1H), 9.25 (s, 1H), 8.38 (s,1H), 8.02 (d, J=8.1 Hz, 2H), 7.58 (d, J=8.5 Hz, 2H), 7.24 (d, J=1.9 Hz,1H), 7.02 (dd, J=1.9, 8.5 Hz, 1H), 6.98 (d, J=8.1 Hz, 1H), 3.81 (s, 3H),2.56 (s, 3H)

Mass, m/z: 384 (M⁺), 166 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, a hydroxyl group, or an alkoxy group), and R′ represents analkyl group.

Example 26-1 Step 26-1-1 2-(4-Chlorophenyl)-4-methyloxazole-5-carboxylicacid hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-3 except that methyl2-(4-chlorophenyl)-4-methyloxazole-5-carboxylate was used instead ofmethyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate.

¹H-NMR (CDCl₃) δ: 9.89 (brs, 1H), 8.17 (d, J=8.5 Hz, 2H), 7.64 (d, J=8.5Hz, 2H), 4.50 (brs, 2H), 2.44 (s, 3H)

Mass, m/z: 251 (M⁺), 164 (base)

Step 26-1-2 2-(4-Chlorophenyl)-4-methyloxazole-5-carboxylic acidN′-(4-hydroxy-3,5-dimethylbenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that2-(4-chlorophenyl)-4-methyloxazole-5-carboxylic acid hydrazide preparedin the Step 26-1-1 and 4-hydroxy-3,5-dimethylbenzaldehyde were usedinstead of 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazideand 3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CDCl₃) δ: 11.63 (brs, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.20 (d,J=8.5 Hz, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.32 (s, 1H), 2.50 (s, 6H), 2.22(s, 3H)

Mass, m/z: 383 (M⁺), 236 (base)

Example 26-2 2-(2-Methoxyphenyl)-4-methyloxazole-5-carboxylic acidN′-(3-hydroxy-4-methoxybenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inExample 26-1 except that2-(2-methoxyphenyl)-4-methyloxazole-5-carboxylic acid hydrazide and3-hydroxy-4-methoxybenzaldehyde were used instead of2-(4-chlorophenyl)-4-methyloxazole-5-carboxylic acid hydrazide and4-hydroxy-3,5-dimethylbenzaldehyde, respectively.

¹H-NMR (CDCl₃) δ: 11.52 (brs, 1H), 9.29 (s, 1H), 8.36 (brs, 1H), 8.04(d, J=8.1 Hz, 1H), 7.60-7.55 (m, 1H), 7.26-7.23 (m, 2H), 7.13 (t, J=7.3Hz, 1H), 7.06 (dd, J=1.9, 8.5 Hz, 1H), 6.99 (d, J=8.5 Hz, 1H), 3.90 (s,3H), 3.82 (s, 3H), 2.47 (s, 3H)

Mass, m/z: 381 (M⁺), 160 (base)

Example 26-3 2-(2-Methoxyphenyl)-4-methyloxazole-5-carboxylic acidN′-(3-methyl-4-methoxybenzyl)-N′-methyl hydrazide

The title compound was obtained according to the same procedure as inExample 26-1 except that2-(2-methoxyphenyl)-4-methyloxazole-5-carboxylic acid hydrazide and3-methyl-4-methoxybenzaldehyde were used instead of2-(4-chlorophenyl)-4-methyloxazole-5-carboxylic acid hydrazide and4-hydroxy-3,5-dimethylbenzaldehyde, respectively.

¹H-NMR (CDCl₃) δ: 11.49 (brs, 1H), 9.84 (s, 1H), 8.36 (brs, 1H), 8.03(d, J=7.3 Hz, 1H), 7.59-7.55 (m, 1H), 7.47 (s, 1H), 7.37 (d, J=7.3 Hz,1H), 7.24 (d, J=8.1 Hz, 1H), 7.12 (t, J=7.3 Hz, 1H), 6.85 (d, J=8.1 Hz,1H), 3.90 (s, 3H), 2.47 (s, 3H), 2.16 (s, 3H)

Mass, m/z: 365 (M⁺), 160 (base)

In the formulae, R and R′ are the same or different and each representan aryl or heterocyclic group which may have a substituent (such as ahalogen atom, an alkyl group, a hydroxyl group, an alkoxy group, or ahaloalkoxy group), and Ts represents a tosyl group.

Example 27-1 Step 27-1-1 (2,4-Dichlorophenyl)-hydroxyiminoacetonitrile

Under an ice cooling, sodium methoxide (2.70 g) was dissolved inmethanol (100 ml), and 2,4-dichlorophenylacetonitrile (9.30 g, 50 mmol)and isoamyl nitrite (5.85 g) were added thereto. The mixture was stirredfor 18 hours at a room temperature. The solvent was distilled off, andthe residue was crystallized by adding diethyl ether (100 ml) to theresidue. The resulting crystal was separated by filtration andazeotropically dried with benzene to give the title compound (9.68 g,90%).

¹H-NMR (DMSO-d₆) δ: 7.70 (d, J=8.9 Hz, 1H), 7.48 (d, J=2.3 Hz, 1H), 7.32(dd, J=2.3, 8.5 Hz, 1H)

Step 27-1-2(2,4-Dichlorophenyl)-O-(p-toluenesulfonyl)hydroxyiminoacetonitrile

To toluene (200 ml), (2,4-dichlorophenyl)-hydroxyiminoacetonitrile (8.60g, 40 mmol) prepared in the Step 27-1-1, tosyl chloride (9.50 g) andtriethylamine (5.0 g) were added, and the mixture was heated underreflux for 5 hours. After being allowed to cool, the mixture was washedwith water and dried over anhydrous magnesium sulfate. The resultingresidue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:3) to give the title compound (11.4 g, 77%).

Step 27-1-3

Ethyl 4-amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylate

In ethanol (100 ml),(2,4-dichlorophenyl)-O-(p-toluenesulfonyl)hydroxyiminoacetonitrile (10.0g, 27.1 mmol) prepared in the Step 27-1-2 was dissolved, andtriethylamine (3.0 g) and ethyl thioglycolate (4.72 g) were addedthereto. The mixture was stirred for one hour at a room temperature. Thesolvent was distilled off. The residue was dissolved in diethyl ether,washed with water, and dried over anhydrous magnesium sulfate. Theresulting residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3) to give the title compound (4.81 g, 56%).

Step 27-1-4 Ethyl 3-(2,4-dichlorophenyl)isothiazole-5-carboxylate

Ethyl 4-amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylate (3.17 g,10.0 mmol) prepared in the Step 27-1-3 was dissolved in tetrahydrofuran(50 ml), and isoamyl nitrite (3.20 g) was added thereto. The mixture washeated and stirred for one hour. The solvent was distilled off, and theresulting residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=1:3) to give the title compound (2.26 g, 75%).

¹H-NMR (DMSO-d₆) δ: 8.25 (s, 1H), 7.82 (d, J=2.3 Hz, 1H), 7.80 (d, J=8.1Hz, 1H), 7.59 (dd, J=2.3 Hz, 1H), 4.40 (q, J=7.3 Hz, 1H), 1.34 (t, J=7.3Hz, 1H)

Mass, m/z: 301 (M⁺, base)

Step 27-1-5 3-(2,4-Dichlorophenyl)isothiazole-5-carboxylic acidhydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-3 except that ethyl3-(2,4-dichlorophenyl)isothiazole-5-carboxylate prepared in the Step27-1-4 was used instead of methyl5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate.

¹H-NMR (CDCl₃) δ: 10.29 and 9.48 (two brs, 1H), 8.24 and 8.22 (two s,1H), 7.81-7.76 (m, 2H), 7.60-7.54 (m, 1H), 5.26 and 4.68 (two brs, 2H)

Mass, m/z: 287 (M⁺), 256 (base)

Step 27-1-6 3-(2,4-Dichlorophenyl)isothiazole-5-carboxylicacid[1-(4-dimethylaminophenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that3-(2,4-dichlorophenyl)isothiazole-5-carboxylic acid hydrazide preparedin the Step 27-1-5 and 4-dimethylaminobenzaldehyde were used instead of5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 12.17 (s, 1H), 8.36 (s, 1H), 8.08 (s, 1H), 7.84 (d,J=8.5 Hz, 1H), 7.81 (d, J=2.3 Hz, 1H), 7.68 (d, J=8.9 Hz, 2H), 7.59 (dd,J=2.3, 8.5 Hz, 1H), 6.84 (d, J=8.9 Hz, 2H), 3.26 (s, 6H)

Mass, m/z: 418 (M⁺), 256, 162, 146 (base)

Examples 27-2 to 27-13

The objective compounds were obtained according to the same procedure asin Example 27-1 except that any one of aldehyde compounds or any one ofacetonitrile compounds shown in the following tables were used insteadof 4-dimethylaminobenzaldehyde or 2,4-dichlorophenylacetonitrile.

TABLE 208 Aceto- nitrile Aldehyde com- Mass, compound pound Example¹H-NMR m/z 4-Difluoro- methoxy- 3-hydroxy benzaldehyde —

(DMS0-d₆) δ: 12.39 (brs, 1H), 10.44 (brs, 1H), 8.37 (s, 1H), 8.12 (s,1H), 7.84 (d, J = 8.1 Hz, 1H), 7.82 (d, J = 1.9 Hz, 1H), 7.65 (d, J =1.5 Hz, 1H), 7.59 (dd, J = 1.9, 8.5 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H),7.20 (dd, J = 1.9, 8.5 Hz, 1H), 7.15 (t, J = 74.8 Hz, 1H) 457 (M⁺), 272,256, 57 (base) 4-Hydroxy-3- methyl benzaldehyde —

(DMS0-d₆) δ: 12.23 (brs, 1H) 10.00 (brs, 1H), 8.37 (s, 1H), 8.09 (s,1H), 7.84 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.59 (dd, J =1.9, 8.5 Hz, 1H), 7.56 (s, 1H), 7.55 (d, J = 7.7 Hz, 1H), 6.94 (d, J =8.1 Hz, 1H), 2.20 (s, 3H) 405 (M⁺), 272, 256, 133, 57 (base) 4-Hydroxy-3,5-dimethyl benzaldehyde —

(DMSO-d₆) δ: 12.23 (s, 1H), 8.90 (s, 1H), 8.37 (s, 1H), 8.07 (s, 1H),7.85 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.59 (dd, J = 2.3,8.5 Hz, 1H), 7.44 (s, 2H), 2.25 (s, 6H) 419 (M⁺), 272, 256, 147 (base)3-Hydroxy-4- methoxy benzaldehyde —

(DMSO-d₆) δ: 12.26 (s, 1H), 9.55 (s, 1H), 8.36 (s, 1H), 8.07 (s, 1H),7.84 (d, J = 8.5 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.59 (dd, J = 1.9,8.5 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 1.9, 8.5 Hz, 1H),7.04 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H) 421 (M⁺), 272, 256, 149 (base)

TABLE 209 Aldehyde Acetonitrile Mass, compound compound Example ¹H-NMRm/z 4-Hydroxy- 3-methyl benzaldehyde 2-Methoxy- phenyl acetonitrile

(DMS0-d₆) δ: 12.14 (s, 1H), 9.97 (s, 1H), 8.48 (s, 1H), 8.07 (s, 1H),7.98 (dd, J = 1.9, 8.5 Hz, 1H), 7.57 (s, 1H), 7.55 (dd, J = 1.9, 7.7 Hz,1H), 7.47 (dt, J = 1.9, 7.7 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.10 (t,J = 7.7 Hz, 1H), 6.94 (d, J = 8.1 Hz, 1H), 3.93 (s, 3H), 2.21 (s, 3H)367 (M⁺), 218, 205 (base), 190 3-Hydroxy- 4-methyl benzaldehyde2-Methoxy- phenyl acetonitrile

(DMS0-d₆) δ: 12.17 (s, 1H), 9.53 (s, 1H), 8.48 (s, 1H), 8.06 (s, 1H),7.99 (dd, J = 1.9, 7.7 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.47 (dt, J =1.9, 7.7 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.15 (dd, J = 1.9, 8.5 Hz,1H), 7.10 (t, J = 7.7 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.94 (s, 3H),3.84 (s, 3H) 383 (M⁺) (base), 218, 205, 190 4-Hydroxy- 3,5-dimethylbenzaldehyde 2-Methoxy- phenyl acetonitrile

(DMS0-d₆) δ: 12.44 (s, 1H), 8.88 (s, 1H), 8.47 (s, 1H), 8.05 (s, 1H),7.99 (dd, J = 1.9, 7.7 Hz, 1H), 7.49-7.45 (m, 1H), 7.44 (s, 2H), 7.22(d, J = 7.7 Hz, 1H), 7.09 (dt, J = 1.2, 7.7 Hz, 1H), 3.93 (s, 3H), 2.25(s, 6H) 381 (M⁺), 218, 205 (base), 190 3-Hydroxy- 4-methoxy benzaldehyde2-Methoxy- phenyl acetonitrile

(DMS0-d₆) δ: 12.19 (s, 1H), 9.54 (s, 1H), 8.20 (s, 1H), 8.07 (s, 1H),7.63 (d, J = 7.3 Hz, 1H), 7.49 (d, J = 1.9 Hz, 1H), 7.40-7.28 (m, 3H),7.15 (dd, J = 1.9, 8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 3.83 (s, 3H),2.48 (s, 3H) 367 (M⁺) (base), 219, 202, 175, 149

TABLE 210 Aldehyde Acetonitrile Mass, compound compound Example ¹H-NMRm/z 4-Hydroxy- 3,5-dimethyl benzaldehyde 2-Methoxy- phenyl acetonitrile

(DMSO-d₆) δ: 12.16 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 8.06 (s, 1H),7.62 (d, J = 7.3 Hz, 1H), 7.44 (s, 2H), 7.40-7.29 (m, 3H), 2.47 (s, 3H),2.25 (s, 6H) 365 (M⁺) (base), 219, 202 174, 147 4-Hydroxy- 3-methylbenzaldehyde 2-Methoxy- phenyl acetonitrile

(DMSO-d₆) δ: 12.16 (s, 1H), 9.98 (s, 1H), 8.20 (s, 1H), 8.08 (s, 1H),7.63 (d, J = 7.3 Hz, 1H), 7.59-7.54 (m, 2H), 7.39-7.29 (m, 3H), 6.94 (d,J = 8.9 Hz, 1 H), 2.48 (s, 3H), 2.20 (s, 3H) 351 (M⁺), 281, 207 (base),133 4-Hydroxy- 3,5-dimethyl benzaldehyde 2-Pyridyl acetonitrile

(DMSO-d₆) δ: 12.19 (s, 1H), 8.90 (s, 1H), 8.71 (dd, J = 1.2, 5.2 Hz,1H), 8.63 (s, 1H), 8.24 (d, J = 8.1 Hz, 1 H), 8.07 (s, 1H), 7.98 (dt, J= 1.5, 7.7 Hz, 1H), 7.51-7.47 (m, 1H), 7.44 (s, 2H), 2.26 (s, 6H) 352(M⁺), 206, 147, 105 (base) 4-Hydroxy- 3,5-dimethyl benzaldehyde(3-Methyl- pyridin- 2-yl) acetonitrile

(DMSO-d₆) δ: 12.15 (s, 1H), 8.89 (s, 1H), 8.56 (s, 1H), 8.55 (d, J = 3.5Hz, 1H), 8.07 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.44 (s, 2H), 7.40 (dd,J = 5.0, 7.7 Hz, 1H), 2.69 (s, 3H), 2.26 (s, 6H) 366 (M⁺), 220, 175, 119(base)

4-Amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylicacid[1-(4-hydroxy-3-methylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 22-1 except that ethyl4-amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylate prepared in theStep 27-1-3 and 4-hydroxy-3-methylbenzaldehyde were used instead ofmethyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.72 (s, 1H), 9.90 (s, 1H), 8.00 (s, 1H), 7.79 (d,J=1.9 Hz, 1H), 7.57 (dd, J=1.9, 8.5 Hz, 1H), 7.53 (s, 1H), 7.51 (d,J=8.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 6.91 (d, 1H), 6.47 (s, 2H), 2.19(s, 3H)

Mass, m/z: 420 (M⁺), 271, 235, 150, 72 (base)

Example 27-15 4-Amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylicacid[1-(4-hydroxy-3,5-dimethylphenyl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 22-1 except that ethyl4-amino-3-(2,4-dichlorophenyl)isothiazole-5-carboxylate prepared in theStep 27-1-3 and 4-hydroxy-3,5-dimethylbenzaldehyde were used instead ofmethyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.72 (s, 1H), 9.81 (s, 1H), 7.98 (s, 1H), 7.79 (d,J=1.9 Hz, 1H), 7.56 (d, J=2.3 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.41 (s,2H), 6.47 (s, 2H), 2.23 (s, 6H)

Mass, m/z: 434 (M⁺), 271, 235, 164, 72 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom or analkoxy group), and R′ represents an alkyl group.

Example 28-1 Step 28-1-1[2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamic acidtert-butyl ester

In tert-butanol (10 ml),2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid (567 mg,2.00 mmol) prepared in Example 7-1 was suspended, and triethylamine (243mg, 2.40 mmol) and then diphenylphosphoryl azide (605 mg, 2.20 mmol)were added thereto. The mixture was heated under reflux for 16 hours.After being allowed to cool, the mixture was concentrated under areduced pressure, and dissolved in chloroform. The resulting solutionwas washed with a saturated sodium bicarbonate solution, and then driedover anhydrous magnesium sulfate and concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give the title compound (1.04 g, quantitative) as awhite powder.

¹H-NMR (DMSO-d₆) δ: 8.16 (d, J=8.5 Hz, 1H), 7.34-7.27 (m, 1H), 7.17-7.12(m, 1H), 4.02 (s, 3H), 2.32 (s, 3H), 1.94 (s, 9H)

Mass, m/z: 354 (M⁺), 298

Step 28-1-2 5-Amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole

In methanol (25 ml),[2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamic acidtert-butyl ester (1.02 g, 2.87 mmol) prepared in the Step 28-1-1 wasdissolved, and a 4-N hydrogen chloride-dioxane solution (25 ml) wasadded thereto. The mixture was stirred at a room temperature for 16hours. Chloroform was added to the mixture, and the resulting mixturewas neutralized with a saturated sodium bicarbonate solution. Theresulting mixture was subjected to extraction with chloroform. Theextract was dried over anhydrous magnesium sulfate and thenconcentrated. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=20:1) to give the title compound(474 mg, 65%) as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 8.04 (d, J=8.5 Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.05(dd, J=2.3, 8.5 Hz, 1H), 5.36 (brs, 2H), 3.96 (s, 3H), 2.18 (s, 3H)

Mass, m/z: 254 (M⁺)

Step 28-1-3 2-(4-Chloro-2-methoxyphenyl)-5-isocyanate-4-methylthiazole

Sodium hydrogen carbonate (240 mg, 2.79 mmol) was dissolved in purifiedwater (10 ml). To this solution, a solution (5 ml) of thiophosgene (240mg, 2.05 mmol) in chloroform was added. Under stirring, a solution (5ml) of 5-amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole (474 mg,1.86 mmol) prepared in the Step 28-1-2 in chloroform was added dropwisethereto, and the mixture was stirred at a room temperature for 4 hours.Chloroform was added to the mixture. The resulting mixture was washedwith a saturated sodium bicarbonate solution, and then dried overanhydrous magnesium sulfate and concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1), crystallized from ethyl acetate-n-hexane, and separated byfiltration. By drying the separated product under a reduced pressure,the title compound (480 mg, 87%) as a light-brown powder was obtained.

¹H-NMR (DMSO-d₆) δ: 8.21 (d, J=8.9 Hz, 1H), 7.38 (d, J=2.3 Hz, 1H), 7.19(dd, J=1.9, 8.5 Hz, 1H), 4.06 (s, 3H), 2.42 (s, 3H)

Mass, m/z: 296 (M⁺, base)

Step 28-1-4[2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]thiocarbamic acidO-(4-methoxybenzyl)ester

In tetrahydrofuran (10 ml),2-(4-chloro-2-methoxyphenyl)-5-isocyanate-4-methylthiazole (100 mg, 0.34mmol) prepared in the Step 28-1-3 was dissolved, and 4-methoxybenzylalcohol (70 mg, 0.51 mmol) was added thereto. The mixture was heatedunder reflux for 15 hours. After being allowed to cool, the mixture waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give the title compound (50 mg, 34%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 8.21 (d, J=8.5 Hz, 1H), 7.32-7.28 (m, 1H), 7.23 (d,J=8.9 Hz, 2H), 7.13 (dd, J=1.9, 8.5 Hz, 1H), 6.88 (d, J=8.9 Hz, 2H),4.16 (s, 2H), 4.04 (s, 3H), 3.28 (s, 3H), 2.34 (s, 3H)

Mass, m/z: 434 (M⁺), 121 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom or analkoxy group), and R′ represents an alkyl group.

Example 29-1 Step 29-1-1 3-Bromo-4-oxopentanoic acid

Concentrated hydrochloric acid (20 ml) was added to 4-oxopentanoic acid(5.0 g), and bromine was added dropwise thereto at −15° C. The mixturewas stirred at a room temperature. After 4 hours, the reaction solutionwas poured into ice water (45 ml). The reaction solution was subjectedto extraction with ethyl ether, and the organic layer was washed with asaturated saline solution, dried over anhydrous magnesium sulfate andthen concentrated under a reduced pressure to give the title compound(7.06 g, 84%).

¹H-NMR (CDCl₃) δ: 4.61 (dd, J=5.4, 8.9 Hz, 1H), 3.32 (dd, J=8.9, 17.7Hz, 1H), 2.94 (dd, J=5.4, 17.7 Hz, 1H), 2.42 (s, 3H)

Mass, m/z: 194 (M⁺), 55 (base)

Step 29-1-2 Ethyl 3-bromo-4-oxopentanoate

Ethanol (100 ml) and concentrated hydrochloric acid (0.05 ml) were addedto 4-oxopentanoic acid (3.0 g) obtained in the Step 29-1-1, and themixture was heated under reflux. After 10 hours, the mixture wasneutralized with a 1-N sodium hydroxide aqueous solution andconcentrated under a reduced pressure. Ethyl acetate was added to theresidue, and the resulting mixture was filtered. The filtrate wasconcentrated under a reduced pressure. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:8) to givethe title compound (1.42 g, 47%).

¹H-NMR (CDCl₃) δ: 4.64 (dd, J=5.8, 8.9 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H),3.25 (dd, J=8.9, 17.0 Hz, 1H), 2.88 (dd, J=5.8, 17.0 Hz, 1H), 2.41 (s,3H), 1.25 (t, J=7.3 Hz, 3H)

Mass, m/z: 221 (M⁺), 101 (base)

Step 29-1-3 Ethyl[2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]acetate

The title compound was obtained according to the same procedure as inthe Step 23-1-1 except that ethyl 3-bromo-4-oxopentanoate obtained inthe Step 29-1-2 and 4-chloro-2-methoxythiobenzamide were used instead ofethyl 2-chloroacetoacetate and 2,4-dichlorothiobenzamide, respectively.

¹H-NMR (CDCl₃) δ: 9.31 (d, J=8.5 Hz, 1H), 7.28 (dd, J=1.9, 8.5 Hz, 1H),7.08 (d, J=1.9 Hz, 1H), 4.27 (q, J=7.3 Hz, 2H), 4.10 (s, 3H), 3.84 (s,2H), 2.82 (s, 3H), 1.33 (t, J=7.3 Hz, 3H)

Mass, m/z: 325 (M⁺), 252 (base)

Step 29-1-4 [2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]aceticacid hydrazide

The title compound was obtained according to the same procedure as inthe Step 23-1-2 except that ethyl[2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]acetate obtained inthe Step 29-1-3 was used instead of ethyl2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylate.

¹H-NMR (DMSO-d₆) δ: 9.27 (s, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.32 (d, J=1.9Hz, 1H), 7.13 (dd, J=1.9 Hz, 8.5 Hz, 1H), 4.27 (s, 2H), 4.03 (s, 3H),3.58 (s, 3H), 2.50 (s, 3H)

Mass, m/z: 311 (M⁺), 252 (base)

Step 29-1-52-(4-Chloro-2-methoxyphenyl)-5-[2-(4-methoxybenzyloxy)ethyl]-4-methylthiazole

The title compound was obtained according to the same procedure as inthe Step 23-1-3 except that[2-(4-chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]acetic acid hydrazideobtained in the Step 29-1-4 and 4-methoxybenzaldehyde were used insteadof 2-(2,4-dichlorophenyl)-4-methylthiazole-5-carboxylic acid hydrazideand 3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (DMSO-d₆) δ: 11.52 and 11.36 (two s, 1H), 8.22 and 8.21 (two d,J=8.5 Hz, 1H), 8.18 and 7.98 (two s, 1H), 7.70 and 7.64 (two d, J=8.9Hz, 2H), 7.32 and 7.28 (d, J=2.3 Hz, 1H), 7.14 and 7.13 (two dd, J=2.3,8.5 Hz, 1H), 7.04 and 7.01 (d, J=8.9 Hz, 2H), 4.16 and 4.03 (two s, 2H),3.92 and 3.78 (two s, 3H), 3.82 and 3.80 (two s, 3H), 2.41 and 2.40 (s,3H)

Mass, m/z: 429 (M⁺), 295, 252, 128, 85 (base)

Example 29-22-(4-Chloro-2-methoxyphenyl)-5-[2-(4-methoxybenzyloxy)ethyl]-4-methylthiazole

The title compound was obtained according to the same procedure as inExample 29-1 except that 4-hydroxy-3,5-dimethylbenzaldehyde was usedinstead of 4-methoxybenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 11.43 and 11.26 (two s, 1H), 8.71 (s, 1H), 8.22 and8.21 (two d, J=8.5 Hz, 1H), 8.04 and 7.87 (two s, 1H), 7.33-7.27 (m,3H), 7.14 and 7.13 (two dd, J=2.3, 8.5 Hz, 1H), 4.15 and 4.03 (two s,2H), 3.93 and 3.76 (two s, 3H), 2.41 and 2.39 (two s, 3H), 2.21 and 2.19(two s, 6H)

Mass, m/z: 443 (M⁺), 295, 252, 128, 85 (base)

In the formulae, R and R′ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, a hydroxyl group, or an alkoxy group).

Example 30-1 Step 30-1-11-[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]-ethanone

3-Chloro-pentane-2,4-dione (540 mg) 4-chloro-thiobenzamide (688 mg) weredissolved in ethanol (10 ml), and the mixture was heated under refluxfor 21 hours. After the mixture was allowed to cool, the precipitatedcrystal was separated by filtration, washed with ethanol, and dried togive the title compound (582 mg, 58%).

¹H-NMR (CDCl₃) δ: 8.02 (dt, J=1.9, 2.7, 8.5 Hz, 2H), 7.60 (dt, J=1.9,2.3, 2.7, 8.8 Hz, 2H), 2.72 (s, 3H), 2.58 (s, 3H)

Mass, m/z: 251 (M⁺), 236 (base)

Step 30-1-2{1-[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]ethylidene}-hydrazine

In ethanol (10 ml), 1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]-ethanone(205 mg) prepared in the Step 30-1-1 was dissolved, and hydrazinemonohydrate (1.2 g) was added thereto. The mixture was heated underreflux for 21 hours. The mixture was concentrated under a reducedpressure, and then water was added thereto. The precipitated crystal wasseparated by filtration, washed with water, and dried to give the titlecompound (196 mg, 91%).

¹H-NMR (DMSO-d₆) δ: 7.88 (dt, J=1.9, 2.7, 8.5 Hz, 2H), 7.53 (dt, J=1.9,2.7, 8.5 Hz, 2H), 6.59 (br, 2H), 2.53 (s, 3H), 2.11 (s, 3H)

Mass, m/z: 265 (M⁺) (base)

Step 30-1-34-{[1-[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]ethylidene]hydrazonomethyl}-2,6-dimethyl-phenol

In ethanol (3 ml),{1-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]ethylidene}-hydrazine (40mg) prepared in the Step 30-1-2 and 4-hydroxy-3,5-dimethylbenzaldehyde(29 mg) was heated under reflux for 20 hours. After the mixture wasallowed to cool, the precipitated crystal was separated by filtration togive the title compound (23 mg, 38%).

¹H-NMR (DMSO-d₆) δ: 8.92 (s, 1H), 8.35 (s, 1H), 7.98 (dt, J=1.9, 2.7,8.5 Hz, 2H), 7.57 (dt, J=1.9, 2.7, 8.5 Hz, 2H), 7.48 (s, 2H), 2.71 (s,3H), 2.59 (s, 3H), 2.22 (s, 6H)

Mass, m/z: 397 (M⁺), 150 (base)

Example 30-24-{[1-[2-(4-Chlorophenyl)-4-methylthiazol-5-yl]ethylidene]hydrazonomethyl}-2,6-dimethyl-phenol

The title compound was obtained according to the same procedure as inExample 30-1 except that 3-hydroxy-4-methoxybenzaldehyde was usedinstead of 4-hydroxy-3,5-dimethylbenzaldehyde.

¹H-NMR (DMSO-d₆) δ: 9.31 (s, 1H), 8.38 (s, 1H), 7.98 (dt, J=2.0, 2.3,2.7, 8.5 Hz, 2H), 7.58 (dt, J=1.9, 2.7, 8.5 Hz, 2H), 7.41 (d, J=1.9 Hz,1H), 7.26 (dd, J=1.9, 8.1 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 3.84 (s, 3H),2.72 (s, 3H), 2.59 (s, 3H)

Mass, m/z: 399 (M⁺), 248 (base)

Example 30-32-Methoxy-5-{[1-[2-(2-methoxyphenyl)-4-methylthiazol-5-yl]ethylidene]hydrazonomethyl}phenol

The title compound was obtained according to the same procedure as inExample 30-1 except that 2-methoxythiobenzamide and3-hydroxy-4-methoxybenzaldehyde were used instead of4-chlorothiobenzamide and 4-hydroxy-3,5-dimethylbenzaldehyde,respectively.

¹H-NMR (DMSO-d₆) δ: 9.29 (s, 1H), 8.41 (s, 1H), 8.31 (dd, J=1.6 Hz,J=7.7 Hz, 1H), 7.50 (ddd, J=1.6 Hz, J=7.3 Hz, J=8.5 Hz, 1H), 7.41 (d,J=2.3 Hz, 1H), 7.26 (dd, J=2.0 Hz, J=8.5 Hz, 2H), 7.12 (td, J=0.8 Hz,J=8.1 Hz, 1H), 7.03 (d, J=8.5 Hz, 1H), 4.05 (s, 3H), 3.84 (s, 3H), 2.72(s, 3H), 2.59 (s, 3H)

Mass, m/z: 395 (M⁺) (base)

Example 31-1 Step 31-1-11-[2-(2,4-Dimethylphenyl)-4-methylthiazol-5-yl]ethanone

To ethanol (20 ml), 2,4-dimethylthiobenzamide (2.00 g) and3-chloropentane-2,4-dione (1.79 g) were added, and the mixture wasstirred under heat reflux for 4 hours. After the mixture was allowed tocool to a room temperature, from the mixture ethanol was distilled offunder a reduced pressure. To the resulting residue, ethyl acetate wasadded, and the mixture was heated and stirred. After the mixture wasallowed to cool to a room temperature, the precipitate was separated byfiltration, washed with ethyl acetate, and then dried under a reducedpressure to give the title compound (1.10 g, 37%).

¹H-NMR (CDCl₃) δ: 8.11 (d, J=7.7 Hz, 1H), 7.25 (d, J=6.2 Hz, 1H), 7.19(s, 1H), 3.08 (s, 3H), 2.65 (s, 3H), 2.63 (s, 3H), 2.39 (s, 3H)

Mass, m/z: 245 (M⁺, base)

Step 31-1-22-[2-(2,4-Dimethylphenyl)-4-methylthiazol-5-yl]-2,2-dimethoxyethanol

To methanol (5 ml),1-[2-(2,4-dimethylphenyl)-4-methylthiazol-5-yl]ethanone (981 mg)prepared in the Step 31-1-1 was added, and a solution of potassiumhydroxide (673 mg) in methanol (10 ml) was added dropwise thereto undercooling by ice and stirring. Thereafter, iodobenzene diacetate (1.42 g)was added to the mixture, and then the resulting mixture was stirred ata room temperature for 22 hours. From the mixture methanol was distilledoff under a reduced pressure, and water was added to the residue. Theresulting mixture was subjected to extraction with dichloromethane. Theextract was dried over anhydrous sodium sulfate, and thendichloromethane was distilled off under a reduced pressure. Hexane wasadded to the residue, the precipitate was separated by filtration,washed with hexane, and then dried under a reduced pressure to give thetitle compound (328 mg, 26%).

¹H-NMR (CDCl₃) δ: 7.64, 7.63 (two d, J=7.7 Hz, 1H), 7.07 (s, 1H), 7.05(dd, J=1.2, 7.7 Hz, 1H), 3.89 (d, J=6.6 Hz, 2H), 3.31 (s, 6H), 2.54 (s,3H), 2.48 (s, 3H), 2.34 (s, 3H), 1.74 (t, J=6.6 Hz, 1H)

Mass, m/z: 307 (M⁺), 276 (base)

Step 31-1-35-[1,1-Dimethoxy-2-(4-methoxybenzyloxy)ethyl]-2-(2,4-dimethylphenyl)-4-methylthiazole

To N,N-dimethylformamide (2 ml),2-[2-(2,4-dimethylphenyl)-4-methylthiazol-5-yl]-2,2-dimethoxyethanol(100 mg) prepared in the Step 31-1-2 and 4-methoxybenzyl chloride (61mg) were added, and 60% sodium hydride suspension in oil (20 mg) wasadded thereto under an argon atmosphere. Then, the mixture was stirredat a room temperature for 4 hours. Ice water was added to the reactionsolution, and then the mixture was subjected to extraction with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thenconcentrated under a reduced pressure. The residue was purified bythin-layer chromatography (hexane:ethyl acetate=3:1) to give the titlecompound (90 mg, 64%).

¹H-NMR (CDCl₃) δ: 7.64 (d, J=7.7 Hz, 1H), 7.09 to 7.04 (m, 4H), 6.78 (d,J=8.8 Hz, 2H), 4.40 (s, 2H), 3.76 (s, 3H), 3.70 (s, 2H), 3.27 (s, 6H),2.56 (s, 3H), 2.34 (s, 6H)

Mass, m/z: 427 (M⁺), 121 (base)

Step 31-1-41-[2-(2,4-Dimethylphenyl)-4-methylthiazol-5-yl]-2-(4-methoxybenzyloxy)ethanone

To dichloromethane (2 ml),5-[1,1-dimethoxy-2-(4-methoxybenzyloxy)ethyl]-2-(2,4-dimethylphenyl)-4-methylthiazole(35 mg) prepared in the Step 31-1-3 was added, and trifluoroacetic acid(0.3 ml) and water (0.1 ml) were added thereto. Thereafter, the mixturewas stirred at a room temperature for 5 hours. To the reaction solution,a saturated sodium bicarbonate solution was added, and then theresulting mixture was subjected to extraction with chloroform. Theextract was washed with a saturated saline solution, and then dried oversodium sulfate and concentrated under a reduced pressure. The residuewas purified by thin-layer chromatography (hexane:ethyl acetate=3:1,toluene:ethyl acetate=3:1) to give the title compound (18 mg, 57%).

¹H-NMR (CDCl₃) δ: 7.71 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.11(s, 1H), 7.09 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.9 Hz, 2H), 4.61 (s, 2H),4.41 (s, 2H), 3.81 (s, 3H), 2.80 (s, 3H), 2.56 (s, 3H), 2.36 (s, 3H)

Mass, m/z: 383 (M⁺), 245 (base)

Example 32-1 Step 32-1 5-(2,4-Dichlorophenyl)-2H-pyrazole-3-carboxylicacid[2-(4-hydroxyphenyl)-ethyl]-amide

In pyridine (6 ml), 4-(2-amino-ethyl)-phenol (72 mg) was dissolved, and5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid chloride (137 mg)was added thereto under an ice cooling while stirring. Thereafter, themixture was stirred at a room temperature for 17 hours and thenconcentrated under a reduced pressure, and the concentrate was purifiedby silica gel column chromatography (5% methanol-chloroform) to give thetitle compound (132 mg, 70%).

¹H-NMR (DMSO-d₆): 13.84 and 13.62 (two s, 1H), 9.15 and 9.14 (two s,1H), 8.62 and 8.16 (t, J=5.4 Hz, 1H), 7.86 and 7.68 (two d, J=8.5 Hz,1H), 7.80 and 7.70 (two d, J=2.3 Hz, 1H), 7.58 and 7.50 (two dd, J=1.9,8.5 Hz, 1H), 7.40 and 6.98 (two d, J=1.6 Hz, 1H), 7.03 (d, J=8.5 Hz,2H), 6.68 (d, J=8.5 Hz, 2H), 3.42 (q, J=7.3 Hz, 2H), 2.73 (q, J=7.7 Hz,2H)

Mass, m/z: 375 (M⁺), 120 (base)

In the formulae, R and R″ are the same or different and each representan aryl group which may have a substituent (such as a halogen atom, analkyl group, a hydroxyl group, or an alkoxy group), and R′ represents analkyl group.

Example 33-1 Step 33-1 3-Hydroxy-4-methoxy-benzoic acidN′-[2-(4-chlorophenyl)-4-methylthiazole-5-carbonyl]hydrazide

In pyridine (4 ml), 2-(4-chloro-phenyl)-4-methyl-thiazole-5-carboxylicacid hydrazide (120 mg) and 3-hydroxy-4-methoxy-benzoyl chloride (84 mg)were stirred for 24 hours at a room temperature. The mixture wasconcentrated under a reduced pressure, and then diluted hydrochloricacid was added thereto. The precipitated crystal was separated byfiltration and dried, and the resulting crystal was recrystallized fromethanol to give the title compound (46 mg, 24%).

¹H-NMR (DMSO-d₆): 10.32 (s, 1H), 10.26 (s, 1H), 9.28 (s, 1H), 8.00 (d,J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.42 (dd, J=1.5, 8.1 Hz, 1H),7.37 (s, 1H), 7.04 (d, J=8.5 Hz, 1H), 3.84 (s, 3H), 2.68 (s, 3H)

Mass, m/z: 417 (M⁺), 151 (base)

In the formulae, Ar represents a thiazole ring which may have an arylgroup as a substituent; R and R′ are the same or different and eachrepresent a halogen atom, an alkyl group, a hydroxyl group or an alkoxygroup; R″ represents an aryl group which may have a substituent (such asan alkoxy group).

Example 34-1 Step 34-1N-[2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]-3-(4-methoxyphenyl)acrylamide

4-Methoxycinnamic acid (178 mg, 1.0 mmol) and thionyl chloride (480 mg,4.0 mmol) were heated under reflux for 2 hours. The excess thionylchloride was distilled off. The resulting residue was dissolved inpyridine (1 ml). Under an ice cooling, the resulting solution was addedto a solution of 5-amino-2-(4-chloro-2-methoxyphenyl)-4-methylthiazole(254 mg, 1.0 mmol) prepared in the Step 28-1-2 in pyridine (4 ml). Afterthe removal of the ice bath, the mixture was stirred for 16 hours at aroom temperature. To the mixture, 3.5% hydrochloric acid was added, andthe resulting mixture was subjected to extraction with chloroform. Theextract was washed with water. The washed product was dried overanhydrous magnesium sulfate, and the solvent was distilled off. Theresulting residue was purified by silica gel column chromatography(chloroform:methanol=30:1) to give the title compound (54 mg, 13%).

¹H-NMR (CDCl₃) δ: 8.25 (d, J=8.5 Hz, 1H), 7.79 (d, J=15.4 Hz, 1H), 7.53(s, 1H), 7.51 (d, 8.5 Hz, 2H), 7.02 (dd, J=1.9, 8.5 Hz, 1H), 6.98 (d,J=1.9 Hz, 1H), 6.91 (d, J=8.9 Hz, 2H), 6.48 (d, J=15.4 Hz, 1H), 4.01 (s,3H), 3.84 (s, 3H), 2.47 (s, 3H)

Mass, m/z: 414 (M⁺), 161 (base)

Example 35-1 Step 35-1-15-(2,4-Dichlorophenyl)-[1,3,4]thiadiazol-2-ylamine

Thiosemicarbazide hydrochloride (2.55 g, 20.0 mmol) was mixed topyridine (20 ml), and 2,4-dichlorobenzoyl chloride (2.81 ml) was addedthereto. The mixture was stirred at a room temperature for 14 hours. Thesolvent was distilled off. Water was added to the resulting residue, andthe mixture was stirred. The precipitate was separated by filtration.2,4-Dichlorobenzoylthiosemicarbazide (2.11 g, 8.00 mmol) obtained fromthe precipitate by through circulation drying was mixed to toluene (25ml), and methanesulfonic acid (0.78 ml) was added to the mixture. Theresulting mixture was heated and stirred for 6 hours. The mixture wasallowed to cool to a room temperature. Then, the precipitate wasseparated by filtration, neutralized with water and 25% ammonia water,and stirred for 30 minutes. The precipitate was separated by filtration,washed with water, and subjected to through circulation drying to givethe title compound (1.14 g, 58%) as a white substance.

¹H-NMR (DMSO-d₆) δ: 8.03 (d, J=8.9 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 7.55(dd, J=2.3, 8.5 Hz, 1H), 7.49 (s, 2H)

Mass, m/z: 245, 247 (M⁺), 74 (base)

Step 35-1-2 [5-(2,4-Dichlorophenyl)-[1,3,4]thiadiazol-2-yl]carbamic acid1-methyl-1H-benzimidazol-5-ylmethyl ester

In tetrahydrofuran (20 ml),5-(2,4-dichlorophenyl)-[1,3,4]thiadiazol-2-ylamine (80 mg, 0.33 mmol)was suspended, and phenyl chlorocarbonate (56 mg, 0.36 mmol) andtriethylamine (36 mg, 0.36 mmol) were added thereto. The mixture wasstirred at a room temperature for one hour. To the mixture,(1-methyl-1H-benzimidazol-5-yl)methanol (63 mg, 0.39 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (60 mg, 0.39 mmol) were added, andthe resulting mixture was heated and stirred for one hour. After theresulting mixture was allowed to cool, the precipitate was washed with asmall quantity of chloroform to give the title compound (20 mg, 14%) asa light-brown substance.

¹H-NMR (DMSO-d₆) δ: 12.47 (brs, 1H), 8.22 (s, 1H), 8.13 (d, J=8.5 Hz,1H), 7.88 (d, J=2.3 Hz, 1H), 7.76 (s, 1H), 7.61 (dd, J=2.3, 8.5 Hz, 1H),7.60 (d, J=8.1 Hz, 1H), 7.38 (dd, J=1.5, 8.5 Hz, 1H), 5.40 (s, 2H), 3.85(s, 3H)

Mass, m/z: 389 (M⁺-44), 133 (base)

Example 35-2 [5-(2,4-Dichlorophenyl)-[1,3,4]thiadiazol-2-yl]carbamicacid 1-methyl-1H-indazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 35-1 except that (1-methyl-1H-indazol-5-yl)methanol was usedinstead of (1-methyl-1H-benzimidazol-5-yl)methanol.

¹H-NMR (DMSO-d₆) δ: 12.47 (brs, 1H), 8.13 (d, J=8.5 Hz, 1H), 8.09 (d,J=8.5 Hz, 1H), 7.89 (d, J=2.3 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J=8.9 Hz,1H), 7.62 (dd, J=2.3, 8.5 Hz, 1H), 7.49 (dd, J=1.5, 8.5 Hz, 1H), 5.39(s, 2H), 4.06 (s, 3H)

Mass, m/z: 433 (M⁺), 389, 145 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group; andR″ represents an alkyl group.

Example 36-1 Step 36-1-1 Ethyl 2-aminobenzothiazole-6-carboxylate

Ethyl 4-aminobenzoate (23.2 g, 140.4 mmol) and potassium thiocyanate(40.9 g, 420.9 mmol) were dissolved in acetic acid (280 ml), and underan ice cooling, bromine (22.4 g, 140.4 mmol) was slowly added thereto.The mixture was stirred under an ice cooling for 10 minutes and thenstirred at a room temperature overnight. To the mixture, purified waterwas added and then ice was added. Thereafter, the resulting mixture wasneutralized with ammonia water. The precipitate was separated byfiltration, washed with purified water, and then subjected to throughcirculation drying to give the title compound (25.2 g, 81%) as a whitepowder.

¹H-NMR (DMSO-d₆) δ: 8.28 (d, J=1.5 Hz, 1H), 7.87 (brs, 2H), 7.82 (dd,J=1.9, 8.5 Hz, 1H), 7.37 (d, J=8.5 Hz, 1H), 4.29 (q, J=6.9 Hz, 2H), 1.32(t, J=6.9 Hz, 3H)

Mass, m/z: 222 (M⁺), 177 (base)

Step 36-1-2 Ethyl benzothiazole-6-carboxylate

Ethyl 2-aminobenzothiazole-6-carboxylate (7.78 g, 35.0 mmol) prepared inthe Step 36-1-1 was dissolved in tetrahydrofuran (100 ml). Amyl nitrite(8.2 g, 70.0 mmol) was added thereto, and the mixture was heated underreflux. After 1.5 hours, amyl nitrite (3.5 g, 30.0 mmol) was addedthereto, and the resulting mixture was heated under reflux. Afteranother 0.5 hours, amyl nitrite (2.6 g, 22.3 mmol) was added thereto,and the resulting mixture was heated under reflux. After being heatedunder reflux for another 3 hours, the resulting mixture was concentratedunder a reduced pressure. The concentrate was purified by silica gelcolumn chromatography (chloroform:methanol=100:1-20:1, and thenn-hexane:ethyl acetate=3:1) to give the title compound (5.1 g, 70%) as alight-brown powder.

¹H-NMR (DMSO-d₆) δ: 9.60 (s, 1H), 8.84 (d, J=1.5 Hz, 1H), 8.29 (d, J=8.5Hz, 1H), 8.11 (d, J=8.5 Hz, 1H), 4.37 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3Hz, 3H)

Mass, m/z: 207 (M⁺), 162

Step 36-1-3 Benzothiazol-6-ylmethanol

Ethyl benzothiazole-6-carboxylate (2.10 g, 10.0 mmol) prepared in theStep 36-1-2 was dissolved in dichloromethane (80 ml), and under an icecooling, a solution (1.5 mol/L) (20 ml, 30.0 mmol) of diisobutylaluminumhydride in hexane was slowly added thereto. The mixture was stirred at aroom temperature for one hour, and then ethyl acetate (10 ml) and asaturated sodium bicarbonate solution were added to the mixture. Ethylacetate and water were added thereto, the resulting mixture wassubjected to extraction with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and then concentrated. The residue waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:1) to give the title compound (0.61 g, 37%) as ayellowish-brown oily substance.

¹H-NMR (DMSO-d₆) δ: 9.33 (s, 1H), 8.08 (s, 1H), 8.03 (d, J=8.5 Hz, 1H),7.49 (dd, J=1.5, 8.1 Hz, 1H), 5.33 (t, J=5.8 Hz, 1H), 4.65 (d, J=5.8 Hz,2H)

Mass, m/z: 165 (M⁺), 136 (base)

Step 36-1-4 [2-(4-Chloro-2-methylphenyl)-4-methylthiazol-5-yl]carbamicacid benzothiazol-6-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound prepared in Step 36-1-3 was usedinstead of(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol.

¹H-NMR (DMSO-d₆) δ: 10.16 (brs, 1H), 9.43 (s, 1H), 8.26 (s, 1H), 8.17(d, J=8.5 Hz, 1H), 8.13 (d, J=8.5 Hz, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.30(d, J=1.9 Hz, 1H), 7.12 (dd, J=1.9, 8.5 Hz, 1H), 5.36 (s, 2H), 4.01 (s,3H), 2.32 (s, 3H)

Mass, m/z: 445 (M⁺), 401

Examples 36-2 to 36-5

The objective compounds were obtained according to the same procedure asin Example 9-1 except that the carboxylic acids or hydroxy compoundsobtained in Examples or Steps shown in the following table were usedinstead of 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid or(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol.

TABLE 211 Car- Hy- box- droxy ylic com- Mass, acid pound Example ¹H-NMRm/z Ex- am- ple 7-14 Step 36-1-3

(DMSO-d₆) δ: 10.15 (brs, 1H), 9.43 (s, 1H), 8.26 (s, 1 H), 8.13 (d, J =8.5 Hz, 1H), 8.05 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1H), 7.02(s, 1H), 6.88 (d, J = 8.1 Hz, 1H), 5.35 (s, 2H), 3.96 (s, 3H), 2.35 (s,3H), 2.30 (s, 3H) 425 (M⁺), 381 Ex- am- ple 7-15 Step 36-1-3

(DMSO-d₆) δ: 9.94 (brs, 1H), 9.43 (s, 1H), 8.25 (s, 1H), 8.13 (d, J =8.5 Hz, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 6.73(d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3, 8.5 Hz, 1H), 5.34 (s, 2H), 3.97(s, 3H), 3.83 (s, 3H), 2.28 (s, 3H) 441 (M⁺), 395 Ex- am- ple 7-16 Step36-1-3

(DMSO-d₆) δ: 10.17 (brs, 1H), 9.24 (s, 1H), 8.26 (s, 1 H), 8.13 (d, J =8.5 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1 H), 7.55 (d, J = 8.1 Hz, 1H), 7.14(s, 1H), 7.09 (d, J = 8.1 Hz, 1H), 5.36 (s, 2H), 2.31 (s, 3H), 2.31 (s,3H) 409 (M⁺), 365 Ex- am- ple 7-30 Step 36-1-3

(DMSO-d₆) δ: 10.22 (brs, 1H), 9.43 (s, 1H), 8.27 (s, 1 H), 8.13 (d, J =8.5 Hz, 1H), 7.69 (dd, J = 5.8, 8.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 1H),7.21 (dd, J = 2.3, 10.0 Hz, 1H), 7.13 (dt, J = 3.1, 8.5 Hz, 1 H), 5.36(s, 2H), 2.69 (q, J = 7.3 Hz, 2H), 2.53 (s, 3H), 1.18 (t, J = 7.3 Hz,3H) 427 (M⁺), 383

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group.

Example 37-1 Step 37-1-1 2-Methylbenzothiazole-5-carboxylic acid

4-Chloro-3-nitrobenzoic acid (2.02 g, 10.00 mmol), sodium sulfidenonahydrate (7.22 g, 30.00 mmol) and water (5 ml) were suspended, andthe mixture was heated at about 100° C. for 30 minutes. After beingallowed to cool, the mixture was cooled by ice, and acetic anhydride (18ml) and acetic acid (10 ml) were added to the mixture. The resultingmixture was heated under reflux for 2 hours and stirred at a roomtemperature for 15 hours. To the mixture, tap water and then ethylacetate were added, and sulfur was removed by filtration. The ethylacetate layer was washed with a saturated saline solution, and thendried over anhydrous magnesium sulfate and concentrated to give thetitle compound (1.54 g, 80%) as a light-yellow powder.

¹H-NMR (DMSO-d₆) δ: 13.09 (brs, 1H), 8.40 (d, J=1.5 Hz, 1H), 8.16 (d,J=8.1 Hz, 1H), 7.95 (dd, J=1.5, 8.5 Hz, 1H), 2.84 (s, 3H)

Mass, m/z: 193 (M⁺, base)

Step 37-1-2 (2-Methylbenzothiazol-5-yl)methanol

In tetrahydrofuran (20 ml), 2-methylbenzothiazole-5-carboxylic acid(0.97 g, 5.00 mmol) prepared in the Step 37-1-1 was dissolved, andtriethylamine (0.66 g, 6.50 mmol) was added thereto. Under an icecooling, ethyl chloroformate (0.71 g, 6.50 mmol) was added to themixture. Under an ice cooling, the resulting mixture was stirred for 30minutes. Under an ice cooling, sodium borohydride was suspended inethanol (20 ml), and the above reaction solution was slowly added to thesuspension. The mixture was allowed to warm to a room temperature andstirred for one hour. To the mixture, 3-N hydrochloric acid was added,and the resulting mixture was stirred for 10 minutes. Then, chloroformwas added thereto, and the resulting mixture was neutralized with asaturated sodium bicarbonate solution. The chloroform layer was driedover anhydrous magnesium sulfate and then concentrated. The concentratewas purified by silica gel column chromatography (ethylacetate:methanol=20:1 to 10:1) to give the title compound (0.52 g, 58%)as a light-yellow powder.

¹H-NMR (DMSO-d₆) δ: 7.95 (d, J=8.1 Hz, 1H), 7.84 (d, J=0.8 Hz, 1H), 7.35(dd, J=1.5, 8.1 Hz, 1H), 5.28 (brs, 1H), 4.63 (s, 2H)

Mass, m/z: 179 (M⁺), 150 (base)

Step 37-1-3 [2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamicacid 2-methylbenzothiazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound prepared in the Step 37-1-2 wasused instead of(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol.

¹H-NMR (DMSO-d₆) δ: 10.16 (s, 1H), 8.17 (d, J=8.5 Hz, 1H), 8.06 (d,J=8.1 Hz, 1H), 7.99 (s, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.30 (d, J=1.9 Hz,1H), 7.12 (dd, J=1.9, 8.5 Hz, 1H), 5.34 (s, 2H), 4.02 (s, 3H), 2.81 (s,3H), 2.32 (s, 3H)

Mass, m/z: 459 (M⁺), 415, 162 (base)

Examples 37-2 to 37-4

The objective compounds were obtained according to the same procedure asin Example 9-1 except that the carboxylic acids or hydroxy compoundsobtained in Examples or Steps shown in the following table were usedinstead of 2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylicacid or(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol.

TABLE 212 Car- Hy- box- droxy ylic com- Mass, acid pound Example ¹H-NMRm/z Ex- am- ple 7-14 Step 37-1-2

(DMSO-d₆) δ: 10.02 (brs, 1H), 8.07-8.04 (m, 2H), 7.99 (s, 1H), 7.47 (d,J = 7.7 Hz, 1H), 7.02 (s, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.33 (s, 2H),3.95 (s, 3H), 2.81 (s, 3H), 2.35 (s, 3H), 2.30 (s, 3H) 439 (M⁺), 395,162 (base) Ex- am- ple 7-16 Step 37-1-2

(DMSO-d₆) δ: 10.18 (brs, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H),7.55 (d, J = 7.7 Hz, 1H), 7.47 (d, J = 7.3 Hz, 1H), 7.14 (s, 1H), 7.09(d, J = 7.7 Hz, 1H), 5.34 (s, 2H), 2.81 (s, 3H), 2.50 (s, 3H), 2.30 (s,6H) 423 (M⁺), 379, 162 (base) Ex- am- ple 7-7 Step 37-1-2

(DMSO-d₆) δ: 10.31 (s, 1H), 8.06 (d, J = 8.1 Hz, 1H), 7.99 (s, 1H), 7.70(d, J = 8.5 Hz, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H),7.35 (dd, J = 1.9, 8.5 Hz, 1H), 5.35 (s, 2H), 2.81 (s, 3H), 2.53 (s,3H), 2.34 (s, 3H) 443 (M⁺), 399, 162 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group.

Example 38-1 Step 38-1-1 Ethyl4-(4-ethoxycarbonyl-2-nitrophenyl)piperidine-1-carboxylate

Ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.91 mmol) prepared in the Step1-1-1 was dissolved in ethanol (100 ml). To the solution, triethylaminewas added and then ethoxycarbonylpiperazine (49.26 mmol) was added, andthe mixture was stirred at a room temperature for 18 hours. After themixture was concentrated, ethyl acetate was added thereto. The resultingmixture was washed with a saturated sodium bicarbonate solution and asaturated saline solution in order. The washed product was dried overanhydrous magnesium sulfate and then concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethylacetate=2:1-1:1) to give the title compound (17.4 g, quantitative) as ayellowish-brown oily substance.

¹H-NMR (DMSO-d₆) δ: 8.31 (d, J=2.3 Hz, 1H), 8.04 (dd, J=1.9, 8.9 Hz,1H), 7.36 (d, J=8.9 Hz, 1H), 4.31 (q, J=6.9 Hz, 1H), 4.07 (q, J=6.9 Hz,2H), 3.53-3.50 (m, 4H), 3.20-3.18 (m, 4H), 1.32 (t, J=6.9 Hz, 3H), 1.20(t, J=6.9 Hz, 3H)

Mass, m/z: 351 (M⁺)

Step 38-1-2 Ethyl4-(2-amino-4-ethoxycarbonylphenyl)piperazine-1-carboxylate

Ethyl 4-(4-ethoxycarbonyl-2-nitrophenyl)piperidine-1-carboxylate (17.0g, 48.4 mmol) prepared in the Step 38-1-1 was dissolved in methanol (100ml), and palladium 5% on carbon (5.0 g) was added thereto. The mixturewas stirred under a hydrogen flow for 16 hours. The mixture wasfiltered, and the filtrate was concentrated to give the title compound(15.2 g, 98%) as a light-black oily substance.

¹H-NMR (DMSO-d₆) δ: 7.33 (d, J=1.9 Hz, 1H), 7.18 (dd, J=1.9, 8.1 Hz,1H), 6.93 (d, J=8.1 Hz, 1H), 5.03 (s, 2H), 4.24 (q, J=6.9 Hz, 2H), 4.07(q, J=6.9 Hz, 2H), 3.56-3.53 (m, 4H), 2.81 (t, J=5.0 Hz, 4H), 1.29 (t,J=6.9 Hz, 3H), 1.20 (t, J=6.9 Hz, 3H)

Mass, m/z: 321 (M⁺, base)

Step 38-1-3 Diethyl3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2,8-dicarboxylate

Formic acid (0.29 g, 6.22 mmol) and purified water (5 ml) were added toethyl 4-(2-amino-4-ethoxycarbonylphenyl)piperazine-1-carboxylate (2.0 g,6.22 mmol) prepared in the Step 38-1-2. A 30% hydrogen peroxide solution(0.63 g, 18.67 mmol) was further added thereto, and the mixture washeated and stirred at 50° C. Formic acid (2 ml) and 2 ml of a 30%hydrogen peroxide solution were further added to the mixture. Theresulting mixture was stirred for another one hour, then allowed tocool, and stirred. After being cooled to a room temperature, the mixturewas neutralized with a saturated sodium bicarbonate solution andsubjected to extraction with ethyl acetate. The extract was dried overanhydrous magnesium sulfate and then concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethyl acetate=1:1to 1:2) to give the title compound (0.22 g, 11%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 8.19 (d, J=0.8 Hz, 1H), 7.89 (dd, J=1.5, 8.5 Hz,1H), 7.63 (d, J=8.5 Hz, 1H), 4.87 (s, 2H), 4.33 (t, J=7.3 Hz, 2H), 4.25(t, J=5.4 Hz, 2H), 4.14 (t, J=6.9 Hz, 2H), 1.35 (t, J=7.3 Hz, 3H), 1.24(t, J=6.9 Hz, 3H)

Mass, m/z: 317 (M⁺), 288 (base)

Step 38-1-41,2,3,4-Tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylic acid

Diethyl3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2,8-dicarboxylate (500mg, 1.58 mmol) prepared in the Step 38-1-3 was suspended in ethanol (3.2ml), and a 1 mol/L sodium hydroxide aqueous solution (1.6 ml) and thenpurified water (1.6 ml) were added thereto. The mixture was heated underreflux for 48 hours. After being allowed to cool, the mixture wasneutralized with 3-N hydrochloric acid. The precipitate was separated byfiltration and dried to give the title compound (230 mg, 67%) as alight-brown powder.

¹H-NMR (DMSO-d₆) δ: 8.13 (d, J=1.5 Hz, 1H), 7.84 (dd, J=1.5, 8.5 Hz,1H), 7.54 (d, J=8.5 Hz, 1H), 4.10-4.08 (m, 4H), 3.21 (t, J=5.4 Hz, 2H)

Mass, m/z: 217 (M⁺, base)

Step 38-1-5 Ethyl1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

In ethanol (200 ml),1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylic acid(2.94 g, 13.53 mmol) prepared in the Step 38-1-4 was suspended.Concentrated sulfuric acid (10 ml) was added thereto, and the mixturewas heated under reflux for 72 hours. After being allowed to cool, themixture was concentrated under a reduced pressure. The concentrate wasneutralized with a saturated sodium bicarbonate solution and 25% ammoniawater and then subjected to extraction with chloroform. The extract wasdried over anhydrous magnesium sulfate and then concentrated under areduced pressure. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=10:1) to give the title compound(2.78 g, 84%) as a light-yellow powder.

¹H-NMR (DMSO-d₆) δ: 8.15 (d, J=1.2 Hz, 1H), 7.85 (dd, J=1.5, 8.5 Hz,1H), 7.58 (d, J=8.5 Hz, 1H), 4.33 (t, J=6.9 Hz, 2H), 4.11-4.08 (m, 4H),3.22-3.19 (m, 2H), 1.35 (t, J=6.9 Hz, 3H)

Mass, m/z: 245 (M⁺, base)

Step 38-1-6 Ethyl2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate

Ethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(0.98 g, 4.00 mmol) prepared in the Step 38-1-5 was dissolved inmethanol (100 ml), and acetic acid (1.00 ml) and a 37% formaldehydeaqueous solution (1.2 ml) were added thereto. Thereafter, sodiumcyanoborohydride (0.57 g, 9.07 mmol) was added to the mixture, and theresulting mixture was stirred. After 30 minutes, the mixture wasconcentrated under a reduced pressure. Chloroform was added to theconcentrate, and the resulting mixture was washed with a saturatedsodium bicarbonate solution. The washed product was dried over anhydrousmagnesium sulfate and concentrated. The concentrate was purified bysilica gel column chromatography (chloroform:methanol=10:1) to give thetitle compound (958 mg, 92%) as a light-brown powder.

¹H-NMR (CDCl₃) δ: 8.42 (d, J=1.2 Hz, 1H), 7.89 (dd, J=1.5, 8.5 Hz, 1H),7.32 (d, J=8.5 Hz, 1H), 4.39 (t, J=6.9 Hz, 2H), 4.16 (t, J=5.4 Hz, 2H),3.88 (s, 2H), 2.98 (t, J=5.4 Hz, 2H), 2.55 (s, 3H), 1.41 (t, J=6.9 Hz,3H)

Mass, m/z: 259 (M⁺, base)

Step 38-1-7(2-Methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-yl)methanol

lithium aluminum hydride (0.21 g, 5.40 mmol) was suspended intetrahydrofuran (15 ml), and under an ice cooling, a solution (5 ml) ofethyl2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(0.70 g, 2.70 mmol) prepared in the Step 38-1-6 in tetrahydrofuran wasslowly added dropwise to the suspension. After the mixture was stirredfor 30 minutes under an ice cooling, and a saturated sodium bicarbonatesolution was slowly added to the mixture under an ice cooling. Ethylacetate was slowly added to the resulting mixture, and the precipitatewas removed by filtration. The residue separated by filtration wascarefully washed with chloroform. The washings and the filtrate wereconcentrated together. The concentrate was purified by silica gel columnchromatography (chloroform:methanol=10:1 to 5:1) to give the titlecompound (0.56 g, 96%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.49 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.17 (dd,J=1.2, 8.1 Hz, 1H), 5.10 (t, J=5.8 Hz, 1H), 4.58 (d, J=5.8 Hz, 2H), 4.11(t, J=5.4 Hz, 2H), 3.74 (s, 2H), 2.92 (t, J=5.4 Hz, 2H), 2.45 (s, 3H)

Mass, m/z: 217 (M⁺)

Step 38-1-8 [2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamicacid2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-ylmethylester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound prepared in the Step 38-1-7 wasused instead of(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol.

¹H-NMR (DMSO-d₆) δ: 10.11 (brs, 1H), 8.32 (s, 1H), 8.16 (d, J=8.5, 1H),7.66 (s, 1H), 7.51 (d, J=8.5 Hz, 1H), 7.32-7.30 (m, 2H), 7.12 (dd,J=1.9, 8.5 Hz, 1H), 5.30 (s, 2H), 4.14 (t, J=5.8 Hz, 2H), 4.01 (s, 3H),3.76 (s, 2H), 2.94 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 2.31 (s, 3H)

Mass, m/z: 454 (M⁺-44), 260 (base)

Example 38-2 [2-(2-Methoxy-4-methylphenyl)-4-methylthiazol-5-yl]carbamicacid2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-ylmethylester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound of Example 7-14 and the compoundprepared in the Step 38-1-7 were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol,respectively.

¹H-NMR (DMSO-d₆) δ: 9.96 (brs, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.65 (s,1H), 7.51 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.87(d, J=8.1 Hz, 1H), 5.29 (s, 2H), 4.13 (t, J=5.8 Hz, 2H), 3.96 (s, 3H),3.75 (s, 2H), 2.93 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 2.35 (s, 3H), 1.99(s, 3H)

Mass, m/z: 477 (M⁺), 433, 260 (base)

Example 38-3 [2-(2,4-Dimethylphenyl)-4-methylthiazol-5-yl]carbamic acid2-methyl-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-ylmethylester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound of Example 7-16 and the compoundprepared in the Step 38-1-7 were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol,respectively.

¹H-NMR (DMSO-d₆) δ: 10.11 (brs, 1H), 7.65 (s, 1H), 7.55 (d, J=8.1 Hz,1H), 7.50 (d, J=8.5 Hz, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.14 (s, 1H), 7.09(d, J=8.1 Hz, 1H), 5.29 (s, 2H), 4.14 (t, J=5.8 Hz, 2H), 3.76 (s, 3H),2.93 (t, J=5.8 Hz, 2H), 2.45 (s, 3H), 2.31 (s, 6H)

Mass, m/z: 417 (M⁺-44), 244 (base)

Example 39-1 Step 39-1-1tert-Butyl(8-hydroxymethyl-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2-carboxylate

lithium aluminum hydride (0.16 g, 4.08 mmol) was suspended intetrahydrofuran (5 ml), and under an ice cooling, a solution (5 ml) ofethyl 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine-8-carboxylate(0.50 g, 2.04 mmol) prepared in the Step 38-1-5 in tetrahydrofuran wasslowly added dropwise to the suspension. After the mixture was stirredfor 30 minutes under an ice cooling, a saturated sodium bicarbonatesolution was slowly added to the mixture under an ice cooling. Ethylacetate was slowly added to the resulting mixture, and the precipitatewas removed by filtration. The residue separated by filtration wascarefully washed with chloroform-methanol. The washings and the filtratewere concentrated together. The concentrated residue was suspended inchloroform (50 ml), and di-tert-butyl dicarbonate (0.67 g, 3.06 mmol)and triethylamine (0.57 ml, 4.08 mmol) were added dropwise to thesuspension. After being stirred at a room temperature for 15 hours, themixture was concentrated under a reduced pressure. The concentrate waspurified by silica gel column chromatography (chloroform:methanol=20:1)to give the title compound (0.38 g, 62%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.52 (s, 1H), 7.43 (d, J=8.5 Hz, 1H), 7.19 (dd,J=1.5, 8.5 Hz, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.67 (s, 2H), 4.58 (d, J=5.8Hz, 2H), 4.15 (t, J=5.4 Hz, 2H), 3.91 (t, J=5.4 Hz, 2H), 1.46 (s, 9H)

Mass, m/z: 303 (M⁺), 246 (base)

Step 39-1-2 tert-Butyl8-[2-(2-methoxy-4-methylphenyl)-4-methylthiazol-5-ylcarbamoylmethyl]-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2-carboxylate

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound of Example 7-14 and the compoundprepared in the Step 39-1-1 were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol,respectively.

¹H-NMR (DMSO-d₆) δ: 9.94 (brs, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.68 (s,1H), 7.53 (d, J=8.5 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 6.87(d, J=7.7 Hz, 1H), 5.29 (s, 2H), 4.79 (s, 2H), 4.79-4.59 (m, 2H), 3.96(s, 3H), 3.93-3.91 (m, 2H), 2.35 (s, 3H), 2.28 (s, 3H), 1.46 (s, 9H)

Mass, m/z: 563 (M⁺), 519, 260 (base)

Step 39-1-3 [2-(2-Methoxy-4-methylphenyl)-4-methylthiazol-5-yl]carbamicacid 1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazin-8-ylmethyl ester

In ethyl acetate (5 ml), tert-butyl8-[2-(2-methoxy-4-methylphenyl)-4-methylthiazol-5-ylcarbamoylmethyl]-3,4-dihydro-1H-benzo[4,5]imidazo[1,2-a]pyrazine-2-carboxylate(120 mg, 0.213 mmol) prepared in the Step 39-1-2 was dissolved, and a4-N hydrochloric acid-dioxane solution (5 ml) was added thereto. Themixture was stirred at a room temperature for 2 hours. Ethyl acetate wasadded to the mixture, and the resulting mixture was neutralized with asaturated sodium bicarbonate solution. The resulting mixture wassubjected to extraction with chloroform, and the extract was dried overanhydrous magnesium sulfate and then concentrated. The residue waslightly washed with ethyl acetate-n-hexane (1:1), separated byfiltration, and dried to give the title compound (85 mg, 86%).

¹H-NMR (DMSO-d₆) δ: 9.96 (brs, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.64 (s,1H), 7.49 (d, J=8.1 Hz, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.02 (s, 1H), 6.87(d, J=8.1 Hz, 1H), 5.28 (s, 2H), 4.06 (brs, 3H), 3.96 (s, 3H), 3.32-3.29(m, 2H), 3.20 (t, J=5.4 Hz, 2H), 2.35 (s, 3H), 2.28 (s, 3H)

Mass, m/z: 463 (M⁺), 260 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group.

Example 40-1 Step 40-1-1 Thiomorpholin-3-one

Under an argon flow and under an ice cooling, sodium hydride (60%, 2.0g, 49.9 mmol) was added to n-propanol (100 ml). After being stirred for5 minutes, the mixture was allowed to warm to a room temperature, andethyl thioglycolate (8.0 g, 66.6 mmol) was added thereto. The resultingmixture was stirred for 30 minutes. To the mixture, 2-oxazolidone (2.9g, 33.3 mmol) was added, and the resulting mixture was heated underreflux for 4 hours. The mixture was concentrated, and ethyl acetate wasadded to the concentrate. The resulting mixture was washed with asaturated sodium bicarbonate solution, dried over anhydrous magnesiumsulfate, and concentrated. The resulting concentrate was purified bysilica gel column chromatography (ethyl acetate:methanol=20:1) to givethe title compound (1.0 g, 26%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.79 (brs, 1H), 3.41-3.38 (m, 2H), 3.15 (s, 2H),2.76 (t, J=5.8 Hz, 2H)

Mass, m/z: 117 (M⁺, base)

Step 40-1-2 Ethyl 3-nitro-4-(3-oxothiomorpholin-4-yl)benzoate

Sodium hydride (60%, 171 mg, 4.27 mmol) was suspended in tetrahydrofuran(10 ml), and thiomorpholin-3-one (500 mg, 4.27 mmol) prepared in theStep 40-1-1 was added thereto. The mixture was stirred at a roomtemperature for 5 minutes, and a solution (10 ml) of ethyl4-fluoro-3-nitrobenzoate (910 mg, 4.27 mmol) prepared in the Step 1-1-1in tetrahydrofuran was slowly added to the mixture. The resultingmixture was stirred at a room temperature for 4 hours. The mixture wasconcentrated, and chloroform was added thereto. The resulting mixturewas washed with a saturated sodium bicarbonate solution. The washedproduct was dried over anhydrous magnesium sulfate and thenconcentrated. The residue was purified by silica gel columnchromatography (n-hexane:ethyl acetate=1:1) and washed with methanol togive the title compound (360 mg, 27%) as a yellow powder.

¹H-NMR (DMSO-d₆) δ: 8.39 (d, J=1.9 Hz, 1H), 8.30 (dd, J=1.9, 8.5 Hz,1H), 7.76 (d, J=8.1 Hz, 1H), 4.38 (q, J=6.9 Hz, 2H), 4.14 (brs, 2H),3.44 (s, 2H), 3.13 (t, J=5.4 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H)

Mass, m/z: 310 (M⁺), 264 (base)

Step 40-1-3 Ethyl 3,4-dihydro-1H-2-thia-4a,9-diazafluorene-7-carboxylate

Ethyl 3-nitro-4-(3-oxothiomorpholin-4-yl)benzoate (2.00 g, 6.44 mmol)prepared in the Step 40-1-2 was dissolved in ethanol (120 ml). Purifiedwater (12 ml), iron powder (2.62 g, 47.04 mmol) and hydrochloric acid(0.5 ml) was added to the solution, and the mixture was heated underreflux for 4 hours. The mixture was concentrated, and a saturated sodiumbicarbonate solution was added thereto, and the resulting mixture wassubjected to extraction with chloroform. The extract was dried overanhydrous magnesium sulfate and then concentrated. The concentrate waspurified by silica gel column chromatography (n-hexane:ethylacetate=1:2) to give the title compound (0.90 g, 53%) as a light-yellowpowder.

¹H-NMR (DMSO-d₆) δ: 8.17 (d, J=1.5 Hz, 1H), 7.88 (dd, J=1.5, 8.5 Hz,1H), 7.61 (d, J=8.5 Hz, 1H), 4.40 (t, J=5.8 Hz, 2H), 4.33 (q, J=6.9 Hz,2H), 4.14 (s, 2H), 3.27 (t, J=5.8 Hz, 2H), 1.35 (t, J=6.9 Hz, 3H)

Mass, m/z: 262 (M⁺), 217 (base)

Step 40-1-4 (3,4-Dihydro-1H-2-thia-4a,9-diazafluoren-7-yl)methanol

Lithium aluminum hydride (76 mg, 2.00 mmol) was suspended intetrahydrofuran (20 ml), and under an ice cooling, a solution (10 ml) ofethyl 3,4-dihydro-1H-2-thia-4a,9-diazafluorene-7-carboxylate (260 mg,1.00 mmol) prepared in the Step 40-1-3 in tetrahydrofuran was slowlyadded to the suspension. After the mixture was stirred under an icecooling for 30 minutes, under an ice cooling, a saturated sodiumbicarbonate solution was slowly added to the mixture, and then ethylacetate was added thereto. The resulting mixture was filtered, and theresidue was washed with a mixture solution of chloroform and methanol.The filtrate was concentrated and purified by silica gel columnchromatography (chloroform:methanol=50:1) to give the title compound(150 mg, 68%) as a white powder.

¹H-NMR (DMSO-d₆) δ: 7.50 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.19 (dd,J=1.2, 8.5 Hz, 1H), 5.12 (t, J=5.8 Hz, 1H), 4.59 (d, J=5.8 Hz, 2H), 4.32(t, J=5.8 Hz, 2H), 4.08 (s, 2H), 3.24 (t, J=5.8 Hz, 2H)

Mass, m/z: 220 (M⁺, base), 191

Step 40-1-5 [2-(4-Chloro-2-methoxyphenyl)-4-methylthiazol-5-yl]carbamicacid 3,4-dihydro-1H-2-thia-4a,9-diazafluoren-7-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound prepared in the Step 40-1-4 wasused instead of(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol.

¹H-NMR (DMSO-d₆) δ: 10.10 (brs, 1H), 8.16 (d, J=8.5 Hz, 1H), 7.67 (s,1H), 7.52 (d, J=8.5 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 7.29 (d, J=1.9 Hz,1H), 7.12 (dd, J=1.9, 8.5 Hz, 1H), 5.30 (s, 2H), 4.35 (t, J=5.8 Hz, 2H),4.10 (s, 2H), 4.02 (s, 3H), 3.30-3.17 (m, 4H), 2.31 (s, 3H)

Mass, m/z: 500 (M⁺), 456, 280, 220 (base)

Example 40-2 [2-(2-Methoxy-4-methylphenyl)-4-methylthiazol-5-yl]carbamicacid 3,4-dihydro-1H-2-thia-4a,9-diazafluoren-7-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound of Example 7-14 and the compoundprepared in the Step 40-1-4 were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol,respectively.

¹H-NMR (DMSO-d₆) δ: 9.95 (brs, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.66 (s,1H), 7.52 (d, J=8.1 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 7.02 (s, 1H), 6.87(d, J=8.1 Hz, 1H), 5.29 (s, 2H), 4.35 (t, J=5.8 Hz, 2H), 4.10 (s, 2H),3.96 (s, 3H), 3.31-3.24 (m, 4H), 2.35 (s, 3H), 2.28 (s, 3H)

Mass, m/z: 480 (M⁺), 436, 260 (base)

Example 40-3 [2-(4-Chloro-2-methylphenyl)-4-methylthiazol-5-yl]carbamicacid 3,4-dihydro-1H-2-thia-4a,9-diazafluoren-7-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 9-1 except that the compound of Example 7-7 and the compoundprepared in the Step 40-1-4 were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid and(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-ylmethanol,respectively.

¹H-NMR (DMSO-d₆) δ: 10.24 (brs, 1H), 7.71-7.68 (m, 1H), 7.55-7.44 (m,3H), 7.36-7.32 (m, 2H), 5.31 (s, 2H), 4.36 (t, J=5.8 Hz, 2H), 4.11 (s,2H), 3.32-3.25 (m, 4H), 2.53 (s, 3H), 2.32 (s, 3H)

Mass, m/z: 265, 220

Example 41-1 Step 41-1-1 Benzothiazole-6-carboxylic acid

Ethyl benzothiazole-6-carboxylate (1.30 g, 6.28 mmol) prepared in theStep 36-1-2 was suspended in ethanol (10 ml) and a 1 mol/L sodiumhydroxide aqueous solution (10 ml), and the mixture was heated underreflux for 40 minutes. After the mixture was allowed to cool,concentrated hydrobromic acid was added to the mixture, and theresulting mixture was adjusted to pH 4. The precipitate was separated byfiltration, washed with water, and then subjected to through circulationdrying to give the title compound (1.10 g, 98%) as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 13.11 (brs, 1H), 9.58 (s, 1H), 8.81 (d, J=1.5 Hz,1H), 8.17 (d, J=8.5 Hz, 1H), 8.09 (dd, J=1.5, 8.5 Hz, 1H)

Mass, m/z: 179 (M⁺, base), 162

Step 41-1-2 Benzothiazol-6-ylcarbamic acid2-(2,4-dimethylphenyl)-4-methylthiazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 13-1 except that the compound of Example 12-6 and the compoundof the Step 41-1-1 were used instead of[2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol and1-methyl-1H-benzimidazole-5-carboxylic acid, respectively.

¹H-NMR (DMSO-d₆) δ: 10.09 (brs, 1H), 9.23 (s, 1H), 8.32 (d, J=0.8 Hz,1H), 7.99 (d, J=8.9 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 7.54 (d, J=8.1 Hz,1H), 7.17 (s, 1H), 7.12 (d, J=8.1 Hz, 1H), 5.41 (s, 2H), 2.50 (s, 6H),2.32 (s, 3H)

Mass, m/z: 409 (M⁺), 365, 216 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group.

Example 42-1 Step 42-1-1 (2-Methylbenzothiazol-5-yl)carbamic acid2-(2,4-dimethylphenyl)-4-methylthiazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 13-1 except that the compound of Example 12-6 and the compoundof the Step 37-1-1 were used instead of[2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol and1-methyl-1H-benzimidazole-5-carboxylic acid, respectively.

¹H-NMR (DMSO-d₆) δ: 9.98 (brs, 1H), 8.10 (s, 1H), 7.90 (d, J=8.9 Hz,1H), 7.62 (d, J=8.1 Hz, 1H), 7.46 (dd, J=1.9, 8.5 Hz, 1H), 7.17 (s, 1H),7.12 (d, J=7.3 Hz, 1H), 5.40 (s, 2H), 2.77 (s, 3H), 2.47 (s, 3H), 2.50(s, 3H), 2.32 (s, 3H)

Mass, m/z: 423 (M⁺), 379, 216 (base)

Example 42-2 (2-Methylbenzothiazol-5-yl)carbamic acid2-(4-chloro-2-methylphenyl)-4-methylthiazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 13-1 except that the compound of Example 12-8 and the compoundof the Step 37-1-1 were used instead of[2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol and1-methyl-1H-benzimidazole-5-carboxylic acid, respectively.

¹H-NMR (DMSO-d₆) δ: 9.99 (brs, 1H), 8.10 (d, J=0.8 Hz, 1H), 7.90 (d,J=8.5 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.48-7.44 (m, 2H), 7.38 (d, J=8.9Hz, 1H), 5.41 (s, 2H), 2.77 (s, 3H), 2.55 (s, 3H), 2.50 (s, 3H)

Mass, m/z: 443 (M⁺), 399, 236 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group; andR″ represents an alkyl group.

Example 43-1 Step 43-1-13,4-Dihydro-1H-2-thia-4a,9-diazafluorene-7-carboxylic acid

Ethyl 3,4-dihydro-1H-thia-4a,9-diazafluorene-7-carboxylate (0.90 g, 3.43mmol) prepared in the Step 40-1-3 was suspended in ethanol (116 ml) anda 1 mol/L sodium hydroxide aqueous solution (15 ml), and the mixture washeated under reflux for 50 minutes. After being allowed to cool, themixture was adjusted to pH 5 with concentrated hydrobromic acid. Theprecipitate was separated by filtration, washed with water, and thensubjected to through circulation drying to give the title compound (0.70g, 88%) as a light-brown powder.

¹H-NMR (DMSO-d₆) δ: 12.70 (brs, 1H), 8.15 (d, J=1.2 Hz, 1H), 7.87 (dd,J=1.5 Hz, 8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 4.40 (t, J=5.8 Hz, 1H),4.13 (s, 2H), 3.27 (t, J=5.8 Hz, 2H)

Mass, m/z: 234 (M⁺, base)

Step 43-1-2 (3,4-Dihydro-1H-2-thia-4a,9-diazafluoren-7-yl)carbamic acid2-(4-fluoro-2-methylphenyl)-4-methylthiazol-5-ylmethyl ester

The title compound was obtained according to the same procedure as inExample 13-1 except that the compound of Example 12-7 and the compoundof the Step 43-1-1 were used instead of[2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol and1-methyl-1H-benzimidazole-5-carboxylic acid, respectively.

¹H-NMR (DMSO-d₆) δ: 9.71 (brs, 1H), 7.79-7.75 (m, 2H), 7.39 (d, J=8.5Hz, 1H), 7.29-7.23 (m, 2H), 7.15 (dt, J=2.7, 8.5 Hz, 1H), 5.38 (s, 2H),4.29 (t, J=5.8 Hz, 2H), 4.06 (s, 2H), 3.30-3.22 (m, 4H), 2.54 (s, 3H),2.50 (s, 3H) Mass, m/z: 468 (M⁺), 424, 231 (base)

Examples 43-2 to 43-4

The objective compounds were obtained according to the same procedure asin Example 13-1 except that the hydroxy compounds or carboxylic acidsobtained in Examples or Steps shown in the following table were usedinstead of [2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol or1-methyl-1H-benzimidazole-5-carboxylic acid.

TABLE 213 Hy- Car- droxy box- com- ylic Mass, pound acid Example ¹H-NMRm/z Ex- am- ple 12-8 Step 43-1-1

(DMSO-d₆) δ: 9.71 (brs, 1H), 7.77-7.74 (m, 2H), 7.48 (d, J = 1.9 Hz,1H), 7.40-7.37 (m, 2H), 7.28 (dd, J = 1.2, 8.5 Hz, 1H), 5.38 (s, 2H),4.29 (t, J = 5.8 Hz, 2H), 4.06 (s, 2H), 3.30-3.22 (m, 4H), 2.55 (s, 3H),2.50 (s, 3H) 484 (M⁺), 440, 231 (base) Ex- am- ple 12-6 Step 43-1-1

(DMSO-d₆) δ: 9.70 (brs, 1H), 7.74 (s, 1H), 7.62 (d, J = 8.1 Hz, 1H),7.39 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.17 (s, 1H), 7.12(d, J = 7.7 Hz, 1H), 5.37 (s, 2H), 4.29 (t, J = 5.8 Hz, 2H), 4.06 (s,2H), 3.23 (t, J = 5.8 Hz, 2H), 2.50 (s, 3H), 2.48 (s, 3H), 2.32 (s, 3H)420 (M⁺ − 44), 233 (base) Ex- am- ple 12-34 Step 43-1-1

(DMSO-d₆) δ: 9.70 (brs, 1H), 7.79-7.75 (m, 2H), 7.39 (d, J = 8.9 Hz,1H), 7.29-7.24 (m, 2H), 7.15 (dt, J = 2.7, 8.5 Hz, 1H), 5.39 (s, 2H),4.29 (t, J = 5.8 Hz, 2H), 4.06 (s, 2H), 3.30-3.22 (m, 4H), 2.85 (q, J =7.7 Hz, 2H), 2.55 (s, 3H), 1.28 (t, J = 7.7 Hz, 3H) 482 (M⁺), 438, 231(base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom, an alkyl group, or an alkoxy group).

Example 44-1 Step 44-1-15-(4-Chloro-2-methoxyphenyl)-[1,3,4]oxathiazol-2-one

In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (5.67 g, 30.5mmol) prepared in the Step 7-1-1 and chlorocarbonylsulfenyl chloride(4.40 g, 33.6 mmol) were suspended, and the mixture was heated underreflux for 1.5 hours. After being allowed to cool, the mixture wassubjected to extraction with ethyl acetate, and the extract was driedover anhydrous magnesium sulfate and then concentrated. The concentratewas purified by silica gel column chromatography (n-hexane:ethylacetate=7:1) to give the title compound (5.33 g, 71%).

¹H-NMR (DMSO-d₆) δ: 7.76 (d, J=8.5 Hz, 1H), 7.36 (d, J=1.9 Hz, 1H), 7.18(dd, J=1.9, 8.5 Hz, 1H), 3.30 (s, 3H)

Mass, m/z: 243 (M⁺), 169 (base)

Step 44-1-2 Ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylateand ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-4-carboxylate

In toluene (35 ml), 5-(4-chloro-2-methoxyphenyl)-[1,3,4]oxathiazol-2-one(2.00 g, 8.21 mmol) prepared in the Step 44-1-1 and ethyl propiolate(4.00 g, 41.0 mmol) were suspended, and the mixture was heated underreflux for 72 hours. After being allowed to cool, the mixture wassubjected to extraction with ethyl acetate, and the extract was driedover anhydrous magnesium sulfate and then concentrated. The concentratewas purified by silica gel column chromatography (n-hexane:ethylacetate=20:1) to firstly give ethyl3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate (1.00 g, 41%) andto secondly give ethyl3-(4-chloro-2-methoxyphenyl)isothiazole-4-carboxylate (826 mg, 34%).

44-1-2-A: ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate

¹H-NMR (DMSO-d₆) δ: 8.25 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.30 (d, J=1.9Hz, 1H), 7.16 (dd, J=1.9, 8.3 Hz, 1H), 4.39 (q, J=7.3 Hz, 2H), 3.29 (s,3H), 1.34 (t, J=7.3 Hz, 3H)

Mass, m/z: 297 (M⁺), 268 (base)

44-1-2-B:ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-4-carboxylate

¹H-NMR (DMSO-d₆) δ: 9.60 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.18 (d, J=1.9Hz, 1H), 7.11 (dd, J=1.9, 8.1 Hz, 1H), 4.14 (q, J=7.3 Hz, 2H), 3.71 (s,3H), 1.13 (t, J=7.3 Hz, 3H)

Mass, m/z: 297 (M⁺), 224 (base)

Step 44-1-3 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylic acid

Ethyl 3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate (500 mg,1.68 mmol) prepared in the Step 44-1-2-A was suspended in ethanol (10ml), and 1 mol/L sodium hydroxide (10 ml) was added thereto. The mixturewas heated under reflux for one hour. After being allowed to cool, themixture was neutralized with hydrochloric acid, and then separated byfiltration and washed with water. The washed product was subjected tothrough circulation drying to give the title compound (194 mg, 43%).

¹H-NMR (DMSO-d₆) δ: 14.11 (brs, 1H), 8.20 (s, 1H), 7.94 (d, J=8.5 Hz,1H), 7.30 (d, J=1.9 Hz, 1H), 7.16 (dd, J=1.9, 8.1 Hz, 1H), 3.95 (s, 3H)

Mass, m/z: 269 (M⁺), 240 (base)

Example 44-2 Step 44-1-43-(4-Chloro-2-methoxyphenyl)isothiazole-4-carboxylic acid

The title compound was obtained according to the same procedure as inthe Step 44-1-3 except that ethyl3-(4-chloro-2-methoxyphenyl)isothiazole-4-carboxylate prepared in theStep 44-1-2-B was used instead of ethyl3-(4-chloro-2-methoxyphenyl)isothiazole-5-carboxylate.

¹H-NMR (DMSO-d₆) δ: 14.11 (brs, 1H), 8.20 (s, 1H), 7.94 (d, J=8.5 Hz,1H), 7.30 (d, J=1.9 Hz, 1H), 7.16 (dd, J=1.9, 8.1 Hz, 1H), 3.95 (s, 3H)

Mass, m/z: 269 (M⁺), 240 (base)

Example 44-3 3-(2-Methoxy-4-methylphenyl)isothiazole-5-carboxylic acid

The title compound was obtained according to the same procedure as inExample 44-1 except that 4-methyl-2-methoxybenzamide was used instead of4-chloro-2-methoxybenzamide.

¹H-NMR (DMSO-d₆) δ: 8.19 (s, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.03 (s, 1H),6.90 (d, J=7.7 Hz, 1H), 3.90 (s, 3H), 2.37 (s, 1H)

Mass, m/z: 249 (M⁺), 220 (base)

Example 44-4 3-(2-Methoxyphenyl)isothiazole-5-carboxylic acid

The title compound was obtained according to the same procedure as inExample 44-1 except that 2-methoxybenzamide was used instead of4-chloro-2-methoxybenzamide.

¹H-NMR (DMSO-d₆) δ: 14.05 (brs, 1H), 8.22 (s, 1H), 7.91 (dd, J=1.5, 7.7Hz, 1H), 7.48 (t, J=8.9 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.09 (t, J=7.7Hz, 1H), 3.92 (s, 3H)

Mass, m/z: 235 (M⁺), 206 (base)

Example 44-5 3-(2-Methoxyphenyl)isothiazole-4-carboxylic acid

The title compound was obtained according to the same procedure as inExample 44-2 except that 2-methoxybenzamide was used instead of4-chloro-2-methoxybenzamide.

¹H-NMR (DMSO-d₆) δ: 12.70 (brs, 1H), 9.51 (s, 1H), 7.44-7.35 (m, 2H),7.08-6.99 (m, 2H), 3.69 (s, 3H)

Mass, m/z: 235 (M⁺, base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group.

Examples 45-1 to 45-7

The objective compounds were obtained according to the same procedure asin Example 9-1 except that the carboxylic acids or hydroxy compoundsobtained in Examples shown in the following tables were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid or(1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-7-yl)methanol.

TABLE 214 Car- Hy- box- droxy ylic com- Mass, acid pound Example ¹H-NMRm/z Ex- am- ple 44-3 Ex- am- ple 3-6

(DMSO-d₆) δ: 11.5 (s, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.70 (s, 1 H), 7.56(d, J = 8.1 Hz, 1H), 7.34 (dd, J = 1.3, 8.3 Hz, 1H), 7.29 (s, 1H), 6.96(s, 1H), 6.85 (dd, J = 1.5, 8.4 Hz, 1H), 5.36 (s, 2H), 4.96 (s, 2H),4.21-4.15 (m, 4H), 3.90-3.84 (m, 4H), 2.34 (s, 3H) 406 (M⁺ − 44), 187(base) Ex- am- ple 44-1 Ex- am- ple 1-1

(DMSO-d₆) δ: 11.6 (s, 1H), 8.21 (s, 1H), 7.90 (d, J = 8.5 Hz, 1 H), 7.75(s, 1H), 7.60 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 1.3, 8.3 Hz, 1H), 7.29(s, 1H), 7.22 (d, J = 1.9 Hz, 1H), 7.10 (dd, J = 1.9, 8.5 Hz, 1H), 5.37(s, 2H), 3.89 (s, 3H), 3.85 (s, 3H) 428 (M⁺), 145 (base) Ex- am- ple44-1 Ex- am- ple 1-2

(DMSO-d₆) δ: 11.5 (s, 1H), 8.28 (s, 1H), 7.90 (d, J = 8.5 Hz, 1 H), 7.75(s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.36 (dd, J = 1.2, 8.5 Hz, 1H), 7.29(s, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.10 (dd, J = 1.9, 8.5 Hz, 1H), 4.29(q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 1.41 (t, J = 7.3 Hz, 3H) 442 (M⁺),159 (base) Ex- am- ple 44-1 Ex- am- ple 4-3

(DMSO-d₆) δ: 11.6 (s, 1H), 8.09 (s, 1H), 7.90 (d, J = 8.5 Hz, 1 H), 7.85(s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 1.3, 8.7 Hz, 1H), 7.29(s, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.09 (dd, J = 1.9, 8.5 Hz, 1H), 5.36(s, 2H), 4.44 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 1.39 (t, J = 7.3 Hz,3H) 442 (M⁺), 159 (base)

TABLE 215 Car- Hy- box- droxy ylic com- Mass, acid pound Example ¹H-NMRm/z Ex- am- ple 44-2 Ex- ample 1-1

(DMSO-d₆) δ: 9.06 (brs, 1H), 8.89 (s, 1H), 8.18 (s, 1H), 7.67 (s, 1H),7.55 (d, J = 8.5 Hz, 1H), 7.29-7.25 (m, 2 H), 7.17 (d, J = 1.9 Hz, 1H),7.05 (dd, J = 1.9, 8.2 Hz, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 3.71 (s, 3H)428 (M⁺), 145 (base) Ex- am- ple 44-5 Ex- ample 1-1

(DMSO-d₆) δ: 8.88 (s, 1H), 8.81 (brs, 1H), 7.67 (s, 1H), 7.54 (d, J =8.1 Hz, 1H), 7.46-7.41 (m, 1H), 7.30-7.26 (m, 2H), 7.11 (d, J = 8.5 Hz,1H), 7.02 (t, J = 7.3 Hz, 1H), 5.22 (s, 2H), 3.83 (s, 3H), 3.70 (s, 3H)394 (M⁺), 145 (base) Ex- am- ple 44-2 Ex- ample 4-3

(DMSO-d₆) δ: 9.05 (brs, 1H), 8.89 (s, 1H), 8.05 (s, 1H), 7.76 (s, 1H),7.66 (d, J = 8.5 Hz, 1H), 7.38 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.1 Hz,1H), 7.17 (d, J = 1.9 Hz, 1 H), 7.05 (dd, J = 1.9, 8.1 Hz, 1H), 5.21 (s,2H), 4.43 (q, J = 7.3 Hz, 2H), 3.70 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H)442 (M⁺), 159 (base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom, an alkyl group, or an alkoxy group); and R′represents a hydrogen atom or an alkyl group.

Examples 46-1 to 46-4

The objective compounds were obtained according to the same procedure asin Example 12-1 except that the carboxylic acids or esters obtained inExamples shown in the following table were used instead of2-(4-chloro-2-methoxyphenyl)-4-methylthiazole-5-carboxylic acid.

TABLE 216 Carboxylic acid or ester Example ¹H-NMR Mass, m/z Example 27-1

(DMSO-d₆) δ: 7.77-7.72 (m, 1H), 7.57-7.53 (m, 2H), 5.95 (t, J = 5.8 Hz,1H), 4.88 (d, J = 5.8 Hz, 2 H) 259 (M⁺, base) Example 44-1

(DMSO-d₆) δ: 7.89 (d, J = 8.7 Hz, 1H), 7.65 (s, 1H), 7.25 (d, J = 1.9Hz, 1H), 7.11 (dd, J = 1.9, 8.2 Hz, 1H), 5.87 (t, J = 5.8 Hz, 1H),4.87-4.85 (m, 2H), 3.91 (s, 3H) 255 (M⁺), 226 (base) Example 44-3

(DMSO-d₆) δ: 7.77 (d, J = 7.7 Hz, 1H), 7.62 (s, 1H), 6.98 (s, 1H), 6.86(d, J = 7.7 Hz, 1H), 5.83 (br s, 1H), 4.85 (s, 2H), 3.86 (s, 3H), 2.36(s, 3H) 235 (M⁺), 206 (base) Example 44-4

(DMSO-d₆) δ: 7.87 (dd, J = 1.9, 7.7 Hz, 1H), 7.65 (s, 1 H), 7.65-7.39(m, 1H), 7.16 (d, J = 8.1 Hz, 1 H), 7.07-7.02 (m, 1H), 5.85 (t, J = 5.4Hz, 1 H), 4.86 (d, J = 5.1 Hz, 2H), 3.30 (s, 3H) 221 (M⁺), 192 (base)

In the formulae, R and R′ are the same or different and each represent ahalogen atom, an alkyl group, a hydroxyl group or an alkoxy group; andR″ represents a heterocyclic group which may have a substituent (such asan alkyl group).

Examples 47-1 to 47-12

According to the production processes shown in the following tables, thehydroxy compounds or carboxylic acids obtained in Examples shown in thefollowing tables were used instead of[2-(2-methylphenyl)-4-methylthiazol-5-yl]methanol or1-methyl-1H-benzimidazole-5-carboxylic acid to give the objectivecompounds.

TABLE 217 Hy- Car- Pro- droxy box- duc- com- ylic tion Mass, pound acidprocess Example ¹H-NMR m/z Ex- am- ple 46-1 — Ex- am- ple 13-1

(DMSO-d₆) δ: 9.84 (s, 1H), 8.12 (s, 1H), 7.84-7.74 (m, 4H), 7.56 (dd, J= 2.3, 8.5 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H),5.55 (s, 2H), 3.81 (s, 3H) 432 (M⁺), 173 (base) Ex- am- ple 46-4 — Ex-am- ple 13-1

(DMSO-d₆) δ: 9.82 (brs, 1H), 8.12 (s, 1H), 7.90 (s, 1 H), 7.88 (d, J =1.9 Hz, 1H), 7.81 (brs, 1H), 7.48 (d, J = 8.5 Hz, 1H), 7.46-7.42 (m,1H), 7.34 (d, J = 8.5 Hz, 1H), 7.18 (d, J = 8.1 Hz, 1H), 7.08-7.04 (m,1H), 5.53 (s, 2H), 3.89 (s, 3H), 3.81 (s, 3H) 394 (M⁺), 173 (base) Ex-am- ple 46-3 — Ex- am- ple 13-1

(DMSO-d₆) δ: 9.80 (brs, 1H), 8.12 (s, 1H), 7.87 (s, 1 H), 7.81 (brs,1H), 7.79 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.34 (d, J =8.5 Hz, 1H), 7.00 (s, 1H), 6.87 (d, J = 7.7 Hz, 1H), 5.52 (s, 2H), 3.88(s, 3H), 3.81 (s, 3H), 2.36 (s, 3H) 408 (M⁺), 173 (base) Ex- am- ple46-2 — Ex- am- ple 13-1

(DMSO-d₆) δ: 9.82 (brs, 1H), 8.12 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H),7.81 (brs, 1H), 7.48 (d, J = 8.9 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.27(d, J = 1.9 Hz, 1H), 7.12 (dd, J = 1.9, 8.5 Hz, 1H), 5.53 (s, 2H), 3.93(s, 3H), 3.81 (s, 3H) 428 (M⁺), 173 (base)

TABLE 218 Pro- Hy- Car- duc- droxy box- tion com- ylic proc- Mass, poundacid ess Example ¹H-NMR m/z Ex- am- ple 46-4 Ex- am- ple 11-7 Ex- am-ple 13-1

(DMSO-d₆) δ: 9.75 (brs, 1H), 7.90-7.87 (m, 2H), 7.70 (brs, 1H),7.46-7.41 (m, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H),7.18 (d, J = 8.1 Hz, 1H), 7.06 (t, J = 7.3 Hz, 1H), 5.52 (s, 2H), 4.06(t, J = 6.2 Hz, 2H), 3.90 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.06-1.88(m, 4H) 434 (M⁺, 213 (base) Ex- am- ple 46-3 Ex- am- ple 11-7 Ex- am-ple 13-1

(DMSO-d₆) δ: 9.75 (brs, 1H), 7.86 (s, 1H), 7.79 (d, J = 7.7 Hz, 1H),7.70 (brs, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.00(s, 1H), 6.87 (d, J = 8.5 Hz, 1H), 5.51 (s, 2H), 4.05 (t, J = 6.2 Hz,2H), 3.88 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.36 (s, 3H), 2.06-1.88 (m,4H) 448 (M⁺), 213 (base) Ex- am- ple 46-2 Ex- am- ple 11-7 Ex- am- ple13-1

(DMSO-d₆) δ: 9.76 (brs, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H),7.70 (brs, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 1.9 Hz, 1H),7.27-7.22 (m, 1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.52 (s, 2H), 4.05(t, J = 6.2 Hz, 2H), 3.93 (s, 3H), 2.93 (t, J = 6.2 Hz, 2H), 2.06-1.88(m, 4H) 468 (M⁺), 213 (base) Ex- am- ple 46-1 Ex- am- ple 11-5 Ex- am-ple 11-7

(DMSO-d₆) δ: 9.78 (brs, 1H), 7.84 (s, 1H), 7.79 (d, J = 2.3 Hz, 1H),7.76 (d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 7.56 (dd, J = 2.3, 8.5 Hz, 1H),7.36 (d, J = 8.5 Hz, 1H), 7.26-7.23 (m, 1H), 5.53 (s, 2H), 4.05 (t, J =6.2 Hz, 2H), 2.93 (t, J = 6.2 Hz, 2H), 2.06-1.90 (m, 4H) 472 (M⁺), 213(base)

TABLE 219 Pro- Hy- Car- duc- droxy box- tion com- ylic proc- Mass, poundacid ess Example ¹H-NMR m/z Ex- am- ple 46-2 Ex- am- ple 11-5 Ex- am-ple 13-1

(DMSO-d₆) δ: 9.82 (brs, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.89 (s, 1H),7.77 (brs, 1H), 7.44 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 8.9 Hz, 1H), 7.27(d, J = 1.9 Hz, 1H), 7.13 (dd, J = 1.9, 8.5 Hz, 1H), 5.52 (s, 2H), 4.93(s, 2H), 4.15 (s, 4H), 3.93 (s, 3H) 471 (M⁺), 216 (base) Ex- am- ple46-4 Ex- am- ple 11-11 Ex- am- ple 13-1

(DMSO-d₆) δ: 9.86 (brs, 1H), 7.99 (s, 1H), 7.90-7.87 (m, 3H), 7.61 (d, J= 8.9 Hz, 1H), 7.46-7.40 (m, 2H), 7.18 (d, J = 8.5 Hz, 1H), 7.06 (t, J =7.3 Hz, 1H), 5.53 (s, 2H), 4.40 (q, J = 7.3 Hz, 2H), 3.89 (s, 3H), 1.38(t, J = 7.3 Hz, 3H) 408 (M⁺), 160 (base) Ex- am- ple 46-2 Ex- am- ple11-11 Ex- am- ple 13-1

(DMSO-d₆) δ: 9.86 (brs, 1H), 8.00-7.89 (m, 4H), 7.61 (d, J = 9.2 Hz,1H), 7.41 (dd, J = 0.8, 8.5 Hz, 1H), 5.53 (s, 2H), 4.40 (q, J = 7.3 Hz,2H), 3.93 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H) 442 (M⁺), 160 (base) Ex- am-ple 46-1 Ex- am- ple 11-11 Ex- am- ple 13-1

(DMSO-d₆) δ: 9.88 (brs, 1H), 8.00 (s, 1H), 7.90 (brs, 1H), 7.84 (s, 1H),7.79 (d, J = 1.9 Hz, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 9.2 Hz,1H), 7.56 (dd, J = 1.9, 8.5 Hz, 1H), 7.43-7.40 (m, 1H), 5.55 (s, 2H),4.40 (q, J = 7.3 Hz, 2H), 1.38 (t, J = 7.3 Hz, 3H) 446 (M⁺), 160 (base)

In the formulae, Ar represents a heterocyclic ring which may have asubstituent (such as an alkyl group).

Example 48-1 Step 48-1-1 1-Ethyl-1H-indazole-5-carbaldehyde

In dichloromethane (10 ml), (1-ethyl-1H-indazol-5-yl)methanol (0.3 g,1.70 mmol) prepared in Example 4-3 was dissolved, and1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.0 g, 2.38mmol) was added thereto. The mixture was stirred for 2 hours. Themixture was subjected to extraction with chloroform, and the extract wasdried over anhydrous magnesium sulfate and then concentrated. Theconcentrate was purified by silica gel column chromatography(dichloromethane:methanol=20:1) to give the title compound.

¹H-NMR (DMSO-d₆) δ: 10.03 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 7.85 (m,2H), 4.49 (m, 2H), 1.42 (t, J=6.9 Hz, 3H)

Mass, m/z: 174 (M⁺), 159 (base)

Example 48-2 3,4-Dihydro-1H-2-oxa-4a,9-diazafluorene-7-carbaldehyde

The title compound was obtained according to the same procedure as inExample 48-1 except that(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)methanol prepared inExample 3-6 was used instead of (1-ethyl-1H-indazol-5-yl)methanol.

¹H-NMR (DMSO-d₆) δ: 10.06 (s, 1H), 8.19 (s, 1H), 7.82 (d, J=8.5 Hz, 1H),7.72 (d, J=8.1 Hz, 1H), 5.01 (s, 2H), 4.28 (t, J=5.2 Hz, 2H), 4.19 (t,J=5.4 Hz, 2H)

Mass, m/z: 202 (M⁺, base)

In the formulae, R represents an aryl group which may have a substituent(such as a halogen atom or an alkoxy group), and R′ represents aheterocyclic group which may have a substituent (such as an alkylgroup).

Example 49-1 Step 49-1-13-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylic acid hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-3 except that the compound prepared in the Step 44-1-2-Awas used instead of methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate.

¹H-NMR (DMSO-d₆) δ: 10.27 and 9.40 (two brs, 1H), 8.34 (d, J=17.0 Hz,1H), 7.95 (t, J=8.5 Hz, 1H), 7.29-7.26 (m, 1H), 7.16-7.12 (m, 1H), 5.19(s, 1H), 4.66 (s, 1H), 3.95 (s, 3H)

Mass, m/z: 283 (M⁺), 252 (base)

Step 49-1-2 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylicacid[1-methyl-1H-benzimidazol-5-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that the compound prepared in the Step 49-1-1 and1-methyl-1H-benzimidazole-5-carbaldehyde were used instead of5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CD₃CO₂D) δ: 9.01 (s, 1H), 8.63 (s, 1H), 8.33-8.25 (m, 3H), 7.99(d, J=8.5 Hz, 1H), 7.86 (d, J=8.9 Hz, 1H), 7.11 (d, J=1.9 Hz, 1H), 7.07(dd, J=1.9, 8.5 Hz, 1H), 4.09 (s, 3H), 3.97 (s, 3H)

Mass, m/z: 425 (M⁺), 157 (base)

Example 49-2 3-(2-Methoxyphenyl)isothiazole-5-carboxylicacid[1-(1-methyl-1H-benzimidazol-5-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 49-1 except that the ester prepared in the process of theproduction of the compound of Example 44-4 was used instead of methyl5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate.

¹H-NMR (CD₃CO₂D) δ: 9.02 (s, 1H), 8.65 (d, J=2.3 Hz, 1H), 8.33-8.28 (m,3H), 8.00 (dd, J=1.5, 7.7 Hz, 1H), 7.87 (d, J=8.5 Hz, 1H), 7.44-7.39 (m,1H), 7.11-7.04 (m, 2H), 4.10 (s, 3H), 3.95 (s, 3H)

Mass, m/z: 391 (M⁺), 204 (base)

Example 49-3 3-(2,4-Dichlorophenyl)isothiazole-5-carboxylicacid[3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that the compound prepared in the Step 27-1-5 andthe compound prepared in Example 48-2 were used instead of5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CD₃CO₂D) δ: 12.39 (s, 1H), 8.40 (s, 1H), 8.35 (s, 1H), 8.05 (s,1H), 7.84 (m, 2H), 7.72 (d, J=8.10 Hz, 1H), 7.60 (d, J=8.2 Hz, 1H), 5.00(s, 2H), 4.26 (m, 2H), 4.19 (m, 2H)

Mass, m/z: 471 (M⁺), 199 (base)

Example 49-4 3-(2-Methoxyphenyl)isothiazole-5-carboxylicacid[1-(3,4-dihydro-1H-2-oxa-4a,9-diazafluoren-7-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 49-1 except that the ester prepared in the process of theproduction of the compound of Example 44-4 and the compound prepared inExample 48-2 were used instead of methyl5-(2-chlorophenyl)-2H-pyrazole-3-carboxylate and1-methyl-1H-benzimidazole-5-carbaldehyde, respectively.

¹H-NMR (CD₃CO₂D) δ: 8.63 (s, 1H), 8.28 (s, 1H), 8.18 (d, J=8.5 Hz, 1H),8.14 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 7.71 (d, J=8.5 Hz, 1H), 7.42 (t,J=7.7 Hz, 1H), 7.11-7.04 (m, 2H), 5.17 (s, 2H), 4.33-4.27 (m, 4H), 3.95(s, 3H)

Mass, m/z: 433 (M⁺), 205 (base)

Example 49-5 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylicacid[1-(3,4-dihydro-1H-2-oxa-4a,9-diaza-fluoren-7-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 49-1 except that the compound prepared in Example 48-2 was usedinstead of 1-methyl-1H-benzimidazole-5-carbaldehyde.

¹H-NMR (CD₃CO₂D) δ: 8.64 (s, 1H), 8.32 (s, 1H), 8.21-8.18 (m, 2H), 8.00(d, J=8.1 Hz, 1H), 7.73 (d, J=8.9 Hz, 1H), 7.12 (d, J=1.2 Hz, 1H), 7.08(dd, J=1.7, 8.3 Hz, 1H), 5.18 (s, 2H), 4.35-4.27 (m, 4H), 3.97 (s, 3H)

Mass, m/z: 467 (M⁺), 199 (base)

Example 49-6 3-(2,4-Dichlorophenyl)isothiazole-5-carboxylicacid[1-(1-ethyl-1H-indazol-5-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inthe Step 22-1-4 except that the compound prepared in the Step 27-1-5 andthe compound prepared in Example 48-1 were used instead of5-(2-chlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide and3-hydroxy-4-methoxybenzaldehyde, respectively.

¹H-NMR (CD₃CO₂D) δ: 8.54 (s, 1H), 8.29 (s, 1H), 8.25 (s, 1H), 8.23 (dd,J=1.5 Hz, J=9.1 Hz, 1H), 8.17 (s, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.72 (d,J=8.9 Hz, 1H), 7.59 (d, J=2.3 Hz, 1H), 7.44 (dd, J=1.9, 8.5 Hz, 1H),4.55 (q, J=7.3 Hz, 2H), 1.50 (t, J=7.3 Hz, 3H)

Mass, m/z: 443 (M⁺), 171 (base)

Example 49-7 3-(2-Methoxyphenyl)isothiazole-5-carboxylicacid[1-(1-ethyl-1H-indazol-5-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 49-1 except that the ester in the process of the production ofthe compound of Example 44-4 and the compound prepared in Example 48-1were used instead of methyl 5-(2-chlorophenyl)-2H-pyrazole-3-carboxylateand 1-methyl-1H-benzimidazole-5-carbaldehyde, respectively.

¹H-NMR (CD₃CO₂D) δ: 8.64 (s, 1H), 8.27-8.24 (m, 3H), 8.16 (s, 1H), 7.99(dd, J=1.7, 7.5 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.42 (m, 1H), 7.10 (d,J=8.9 Hz, 1H), 7.06 (d, J=7.7 Hz, 1H), 4.54 (q, J=7.3 Hz, 2H), 3.95 (s,3H), 1.50 (t, J=7.3 Hz, 3H)

Mass, m/z: 405 (M⁺), 171 (base)

Example 49-8 3-(4-Chloro-2-methoxyphenyl)isothiazole-5-carboxylicacid[1-ethyl-1H-indazol-5-yl)methylidene]hydrazide

The title compound was obtained according to the same procedure as inExample 49-1 except that the compound prepared in Example 48-1 was usedinstead of 1-methyl-1H-benzimidazole-5-carbaldehyde.

¹H-NMR (CD₃CO₂D) δ: 8.63 (s, 1H), 8.27-8.22 (m, 3H), 8.16 (s, 1H), 8.00(d, J=8.1 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.11 (s, 1H), 7.08 (dd,J=1.5, 9.2 Hz, 1H), 4.54 (q, J=7.3 Hz, 2H), 3.97 (s, 3H), 1.50 (t, J=7.3Hz, 3H)

Mass, m/z: 439 (M⁺), 171 (base)

Pharmacological Test Procedure and Test Results

Hereinafter, the pharmacological test procedure for the validity(usefulness) of the heterocyclic compound or the salt thereof of thepresent invention and the results thereof will be explained.

Test Example 1 Measurement of Cell Death-Inducing Activity

The cell death-inducing activity of the compound represented by theformula (1) or the salt thereof was measured as follows.

Human prostate cancer cell lines (PC-3 cells) were seeded to 6-wellplates at 1×10⁵ cells/2 mL/well, and cultured in the presence of 5% CO₂at 37° C. for 48 hours. Thereafter, each compound was added thereto soas to provide 10, 1, 0.1, 0.025 and 0.00625 μmol/L. As a control, DMSOwas added. After the addition, the cells were continuously cultured for48 hours. Then, typical 10 fields were observed in each well toqualitatively evaluate the cell death-inducing rate. When the celldeath-inducing rate was not less than 40%, the compound was judged tohave the cell death-inducing activity.

Results

(1) Compounds (Example Number) Showing the Cell Death-Inducing Activityat a Concentration of 0.00625 μM

Examples 9-15, 9-16, 9-24, 9-25, 9-38, 9-39, 9-40, 9-42, 9-48, 9-49,9-58, 9-59, 9-60, 9-61, 9-62, 9-63, 9-64, 9-92, 9-93, 9-94, 9-96, 9-98,9-103, 9-128, 9-129, 9-136, 9-137, 9-165, 9-169, 9-181, 9-221, 9-222,9-223, 9-224, 9-226, 9-227, 9-228, 9-233, 9-235, 9-247, 9-249, 9-280,9-300, 9-344, 9-372, 13-10, 13-26, 13-80, 13-84, 13-85, 13-86, 13-88,13-89, 13-90, 13-92, 13-97, 13-99, 13-100, 13-101, 13-103, 13-106,13-108, 13-109, 13-110, 13-111, 13-112, 13-113, 13-118, 13-133, 47-3,47-4, 47-7, 47-9

(2) Compounds (Example Number) Showing Cell Death-Inducing Activity at aConcentration of 0.025 μM

Examples 9-1, 9-13, 9-14, 9-17, 9-19, 9-20, 9-22, 9-23, 9-26, 9-27,9-28, 9-33, 9-36, 9-37, 9-41, 9-47, 9-56, 9-57, 9-67, 9-71, 9-76, 9-77,9-78, 9-81, 9-82, 9-86, 9-87, 9-91, 9-95, 9-97, 9-102, 9-106, 9-107,9-108, 9-113, 9-130, 9-134, 9-135, 9-138, 9-139, 9-140, 9-141, 9-143,9-144, 9-145, 9-147, 9-150, 9-153, 9-154, 9-155, 9-160, 9-161, 9-163,9-164, 9-166, 9-167, 9-170, 9-171, 9-172, 9-173, 9-174, 9-176, 9-182,9-207, 9-208, 9-209, 9-213, 9-217, 9-218, 9-219, 9-229, 9-230, 9-234,9-239, 9-245, 9-248, 9-250, 9-251, 9-258, 9-259, 9-260, 9-261, 9-262,9-267, 9-281, 9-283, 9-291, 9-292, 9-301, 9-340, 9-341, 9-345, 9-346,9-349, 9-357, 9-358, 9-359, 9-360, 9-362, 9-364, 9-365, 9-373, 9-377,13-8, 13-9, 13-11, 13-15, 13-16, 13-17, 13-18, 13-24, 13-25, 13-28,13-34, 13-35, 13-50, 13-55, 13-76, 13-81, 13-82, 13-83, 13-87, 13-95,13-98, 13-102, 13-104, 13-105, 13-107, 13-116, 13-119, 13-120, 13-121,13-122, 13-123, 13-129, 13-149, 13-150, 17-2, 23-46, 23-92, 23-171,40-1, 40-2, 43-2, 47-6, 49-1, 49-2

(3) Compounds (Example Number) Showing Cell Death-Inducing Activity at aConcentration of 0.1 μM

Examples 9-3, 9-18, 9-35, 9-46, 9-53, 9-68, 9-70, 9-75, 9-79, 9-80,9-83, 9-88, 9-90, 9-100, 9-101, 9-104, 9-111, 9-112, 9-115, 9-120,9-126, 9-127, 9-131, 9-133, 9-142, 9-146, 9-152, 9-156, 9-157, 9-162,9-168, 9-175, 9-177, 9-185, 9-210, 9-214, 9-215, 9-220, 9-236, 9-242,9-243, 9-246, 9-252, 9-253, 9-256, 9-257, 9-268, 9-269, 9-270, 9-271,9-284, 9-285, 9-286, 9-290, 9-293, 9-295, 9-302, 9-343, 9-348, 9-350,9-352, 9-353, 9-356, 9-361, 9-366, 9-368, 9-370, 9-374, 9-375, 9-376,13-1, 13-3, 13-5, 13-12, 13-13, 13-21, 13-30, 13-33, 13-44, 13-45,13-48, 13-49, 13-53, 13-54, 13-56, 13-67, 13-77, 13-78, 13-91, 13-96,13-114, 13-115, 13-117, 13-127, 13-135, 16-1, 16-6, 16-8, 16-11, 16-13,16-19, 16-20, 16-24, 16-25, 17-1, 21-25, 22-9, 22-10, 23-2, 23-4, 23-7,23-12, 23-14, 23-15, 23-16, 23-17, 23-44, 23-48, 23-50, 23-53, 23-68,23-70, 23-73, 23-74, 23-78, 23-79, 23-82, 23-83, 23-84, 23-88, 23-90,23-91, 23-93, 23-95, 23-97, 23-98, 23-120, 23-122, 23-123, 23-124,23-145, 23-149, 23-153, 23-156, 23-157, 23-158, 23-159, 23-160, 24-3,27-7, 27-8, 27-10, 27-13, 37-1, 39-1, 40-3, 43-1, 43-3, 45-5, 45-7,47-1, 47-5, 47-11

(4) Compounds (Example Number) Showing Cell Death-Inducing Activity at aConcentration of 1 μM

Examples 9-2, 9-12, 9-30, 9-31, 9-32, 9-43, 9-44, 9-45, 9-54, 9-66,9-69, 9-72, 9-74, 9-84, 9-85, 9-99, 9-109, 9-110, 9-121, 9-122, 9-125,9-148, 9-149, 9-151, 9-158, 9-183, 9-184, 9-186, 9-192, 9-193, 9-200,9-203, 9-205, 9-216, 9-231, 9-240, 9-244, 9-254, 9-255, 9-263, 9-264,9-265, 9-266, 9-274, 9-275, 9-276, 9-279, 9-288, 9-289, 9-294, 9-296,9-303, 9-304, 9-305, 9-342, 9-347, 9-351, 9-354, 9-355, 9-363, 9-367,9-369, 9-371, 10-2, 13-19, 13-20, 13-23, 13-27, 13-31, 13-39, 13-41,13-57, 13-68, 13-71, 13-72, 13-93, 13-94, 13-125, 13-128, 13-130,13-131, 13-132, 16-3, 16-4, 16-7, 16-10, 16-12, 16-15, 16-16, 16-17,16-18, 16-21, 16-22, 16-23, 17-3, 18-1, 18-2, 21-7, 21-9, 21-11, 21-19,21-20, 21-21, 21-22, 22-3, 22-6, 22-8, 23-8, 23-13, 23-22, 23-23, 23-26,23-28, 23-34, 23-38, 23-41, 23-43, 23-45, 23-47, 23-52, 23-55, 23-61,23-65, 23-66, 23-67, 23-71, 23-72, 23-75, 23-76, 23-77, 23-80, 23-85,23-89, 23-94, 23-100, 23-104, 23-106, 23-110, 23-115, 23-116, 23-117,23-118, 23-121, 23-125, 23-126, 23-127, 23-128, 23-130, 23-131, 23-134,23-135, 23-136, 23-137, 23-139, 23-140, 23-141, 23-142, 23-143, 23-147,23-161, 23-162, 23-165, 23-166, 23-167, 23-168, 23-171, 23-172, 24-1,24-2, 27-4, 27-5, 27-9, 27-12, 29-1, 29-2, 30-2, 34-1, 36-1, 36-2, 37-2,37-3, 37-4, 38-1, 42-1, 42-2, 43-4, 45-2, 45-6, 47-2, 47-8, 49-5, 49-6,49-7, 49-8

(5) Compounds (Example Number) Showing Cell Death-Inducing Activity at aConcentration of 10 μM

Examples 9-5, 9-7, 9-8, 9-11, 9-21, 9-29, 9-50, 9-55, 9-116, 9-118,9-119, 9-124, 9-178, 9-179, 9-191, 9-195, 9-196, 9-204, 9-211, 9-212,9-238, 9-241, 9-273, 9-277, 9-278, 9-297, 9-298, 9-306, 9-309, 9-311,9-313, 9-320, 9-321, 9-324, 9-335, 9-337, 9-338, 9-339, 13-22, 13-36,13-46, 13-61, 13-66, 13-70, 13-73, 13-124, 13-126, 13-137, 13-141,13-144, 16-2, 16-5, 16-9, 16-14, 17-4, 19-1, 19-2, 20-1, 21-2, 21-6,21-8, 21-13, 21-15, 21-17, 21-18, 22-1, 22-4, 22-7, 23-1, 23-5, 23-6,23-10, 23-11, 23-18, 23-19, 23-20, 23-21, 23-24, 23-27, 23-30, 23-35,23-40, 23-42, 23-51, 23-57, 23-59, 23-60, 23-81, 23-86, 23-101, 23-102,23-103, 23-105, 23-107, 23-108, 23-113, 23-119, 23-129, 23-132, 23-133,23-138, 23-150, 23-152, 23-154, 23-163, 23-169, 23-170, 25-1, 25-2,25-3, 25-4, 25-5, 26-1, 26-2, 26-3, 27-1, 27-2, 27-3, 27-6, 27-11,27-14, 27-15, 27-16, 28-1, 30-1, 31-1, 36-3, 36-4, 36-5, 38-2, 38-3,41-1, 45-1, 45-3, 45-4, 47-10, 47-12, 49-3, 49-4

As apparent from the results, the compound represented by the formula(1) or the salt thereof showed the cell death-inducing activity at eachconcentration. Further, for the compound represented by the formula (1)or the salt thereof, the IC₅₀ values on various cancer cell lines can becalculated by the method of Test Example 2 or other methods.

Test Example 2 Calculation of IC₅₀ Value

Human prostate cancer cell lines (PC-3 cells) and human fibrosarcomacell lines (HT1080 cells) were seeded to 96-well microplates so as toprovide a density of 1,300 cells/well and that of 3,100 cells/well,respectively. In the presence of 5% CO₂ at 37° C., the PC-3 cells andthe HT1080 cells were cultured for 48 hours and 24 hours, respectively.Thereafter, each one of test substances was added to each well. As acontrol of a medical agent, DMSO was added. After the addition, bothcells were continuously cultured for 72 hours. Then, an XTT labelingreagent containing 1 mg/mL of sodium3′-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzenesulfonatehydrate (XTT) and an electronic coupling reagent containing 1.25 mMN-methyl dibenzopyrazine methyl sulfate (PMS) were mixed at a ratio of50:1 to give an XTT labeling mixture. The XTT labeling mixture was addedto each well in an amount of 50 μL per well, and the cells were culturedfor another 4 hours. A culture solution containing a test substance wasused as a blank, and the absorbencies of a culture solution containingthe XTT labeling mixture at a measurement wavelength (450 nm) and acontrol wavelength (650 nm) were measured by a plate reader. Thedifference between these absorbencies was evaluated as an activity ofdehydrogenase of mitochondria derived from living cells. With respect tothe following model formula of sigmoid curve, the convergent solution ofeach variable (gain, range, base and α) that minimize the residual sumof squares of the difference between these absorbencies and regressiveprediction was determined, and then IC₅₀ (=e^(α)) of each test substancewas calculated.

${{Difference}\mspace{14mu} {between}\mspace{14mu} {absorbencies}} = {\frac{range}{1 + ^{{gain}\mspace{11mu} {({{l\; {n{({{Test}\mspace{14mu} {substance}\mspace{14mu} {concentration}})}}} - \alpha})}}} + {base}}$

The IC₅₀ values of the compounds represented by the formula (1) or thesalts thereof on two cancer cell lines according to the method of TestExample 2 were calculated, and the results are shown in Table A.

TABLE A Cell proliferation inhibitory activity (IC₅₀ value calculatedfrom XTT assay) Concentration showing 50% inhibitory activity (nmol/L)Human prostate Human fibrosarcoma Compound cancer cell lines cell linesnumber (PC-3) (HT1080) 9-1  6.70 15.1 9-25  0.81 1.64 9-57  2.17 — 9-94 0.56 1.75 9-155 6.77 — 13-53  6.35 — 13-90  0.43 — 13-101  1.64 4.19

As apparent from Table A, the compounds represented by the formula (1)or the salts thereof have a strong cell proliferation inhibitoryactivity to the cancer cell lines, which suggests the usefulness of thecompounds or salts thereof as antitumor agents.

Test Example 3 Measurement of Expression Kinetics of p27^(Kip1) andOther Substrate Proteins

The possibility that p21^(Cip1), p57^(Kip2) and CyclinD1 are substrateproteins of SCF^(Skp2) has been reported. While, there is also a reportthat gives a suggestion that these proteins may be substrates of anotherE3. The following suggestions about Nrf2 have been given: theprogressive expression of Nrf2 is an index of the acquirement ofresistance by an existing drug (anticancer agent), and Nrf2 is asubstrate protein of another E3. Thus, in order to verify that thecompounds represented by the formula (1) or the salts thereof arep27^(Kip1)-selective degradation inhibitors, these molecules in additionto p27^(Kip1) were used as objects of analysis.

PC-3 cells in logarithmic growth phase (48 hours after seeding) weretreated with 10 to 25 nmol/L of each test substance, then the cells werecollected with time, and the protein was extracted and determinedquantitatively. The protein groups contained in each extract (the amountof protein: 10 to 15 μg) were separated by polyacrylamide gelelectrophoresis and then transferred to a PVDF (polyvinylidenedifluoride) membrane. The proteins in the membrane were allowed to reactwith various primary antibodies to p27^(Kip1), p21^(Cip1), p57^(Kip2),CyclinD1, Nrf2 and β-actin at a room temperature for about 2 hours, thenallowed to further react with a biotinylated secondary antibody at aroom temperature for one hour, and then allowed to react withstreptavidin alkaline phosphatase at a room temperature for 30 minutes.As the final step, the proteins in the membrane were detected byallowing to react with a chemiluminescent substrate containing disodium4-chloro-3-(methoxyspiro{1,2-dioxetadioxetane-3,2′-(5′-chloro)tricyclo[3.3.1.1^(3,7)]decan}-4-yl)phenylphosphate.

Results

As apparent from FIG. 1 to FIG. 3, the compounds represented by theformula (1) or the salts thereof increased only the expression amount ofp27^(Kip1) with time without affecting the expression amounts of otheranalyzed substrate proteins.

Test Example 4 Analysis of Cell Death-Inducing Action

Human prostate cancer cell lines (PC-3 cells) in logarithmic growthphase (48 hours after seeding) were treated with the compoundrepresented by the formula (1) or the salt thereof, then the cells werecollected with time and suspended in 70% ethanol. Thereafter, the cellsin the suspension were allowed to stand at −20° C. overnight or more tobe immobilized. The immobilized cells were washed with PBS twice, 100 μLof 192 mmol/L of disodium hydrogen phosphate and 4 mmol/L of a citricacid solution were added thereto, and the cells were suspended. Theresulting suspension was gently stirred at a room temperature for 30minutes. After centrifugation, the supernatant was removed. Then, 100 μLof a 100 μg/mL RNase/PBS solution was added to the residue, and theresidue was suspended. The resulting suspension was incubated at 37° C.for 30 minutes. To the suspension, 850 μL of PBS was added, and then 50μL of a 1 mg/mL propidium iodide/PBS solution were added thereto. Thereaction was conducted at a room temperature for 30 minutes while gentlystirring the mixture by inverting, and then the reaction mixture wasfiltered through a mesh filter to give an analysis sample. Using a flowcytometer, the ratio of sub-G₁ cells*, as an index of apoptosis cells,was analyzed. *Darzynkiewicz Z, et al. Cytometry, 27: 1-20, (1997) (Thispaper defines that the sub-G₁ cell is an index of an apoptosis cell.)

Results

As apparent from FIG. 1 to FIG. 6, the results suggest that thecompounds represented by the formula (1) or the salts thereofselectively increase the expression amount of p27^(Kip1) and then induceapoptosis.

Test Example 5 Tumor Growth Inhibitory Effect Test Using Tumor Model

0.1 mL (2×10⁵ cells/body) of human prostate cancer cell lines PC-3 wastransplanted into the right infra-axillary dermis of male 6-week-oldnude mice. From 3 days after the transplantation, Vehicle or any one ofthe following compounds was orally administered repeatedly twice a dayfor 11 days. Fourteenth (14) days after the transplantation, the majoraxis and minor axis of the tumor were measured, and the efficacy of eachcompound was evaluated on the basis of the tumor volume (majoraxis×minor axis×height×0.5236).

Results

At a dose of not more than 1 mg/kg, the following compounds (Examplenumbers) showed an antitumor effect at an inhibitory ratio of not lessthan 50% compared with the Vehicle group.

Examples 9-1, 9-25, 9-57, 9-94, 9-145, 9-155, 9-157, 9-213, 9-247,9-281, 13-53, 13-81, 13-90, 13-100, 13-101

Test Examples 1 to 5 suggest that the p27^(Kip1) degradation inhibitorcontaining the compound represented by the formula (1) or thepharmaceutically acceptable salt thereof as an effective ingredient hasa tumor growth inhibitory effect.

Preparation Examples Solid Preparation for Oral Administration

Formulation example: mg/tablet Active ingredient 5.0 Starch 10.0 Lactose73.0 Carboxymethyl cellulose calcium 10.0 Talc 1.0 Magnesium stearate1.0 Total amount 100.0

Granule

The active ingredient [the compound represented by the formula (1) orthe salt thereof] was pulverized to a grain size of not more than 70 μm,and a starch, a lactose and a carboxymethyl cellulose calcium were mixedwith the pulverized powder fully. Thereafter, 10% starch glue was mixedwith the mixture powder under stirring, and the resulting mixture wassubjected to wet granulation to give a granule.

Tablet

The particle size of the granule obtained by the above step was sizedaround 1000 μm, and a talc and magnesium stearate were mixed thereto.The resulting mixture was subjected to tablet compression to give atablet.

Capsule

The granule obtained by the above step was filled into a hard capsuleshell to give a capsule.

Injectable Solution

The active ingredient [the compound represented by the formula (1) orthe salt thereof] (50 mg) was dissolved in 100 ml of a physiologicalsaline containing ethanol as a solubilizing agent, and the resultingsolution was filled in a container. The container was sealed. Then, thesealed container was sterilized to give an injectable solution.

INDUSTRIAL APPLICABILITY

The compound or the salt thereof of the present invention specificallybinds to Skp2 of ubiquitin ligase (SCF^(Skp2)) and, for example,inhibits the dissociation of p27^(Kip1) from SCF^(Skp2) complex. Thusthe compound or the salt thereof of the present invention is useful asan inhibitor for the ubiquitination and degradation of p27^(Kip1).Moreover, since the compound or the salt thereof of the presentinvention can recover the expression amount of p27^(Kip1) in cellshaving a decreased expression of p27^(Kip1) to induce cell death(apoptosis), the compound or the salt thereof is also useful as an agentfor preventing and/or treating a cell proliferative disease (forexample, cancer, rheumatism, diabetes, adiposis, endometriosis,prostatomegaly, and inflammation). In particular, the possibleapplication of the compound or the salt thereof as an anticancer agentto not only a cancer of the prostate but also a highly malignant solidcancer (e.g., a cancer of the lung, a cancer of the large intestine, acancer of the liver, a cancer of the stomach, a cancer of the uterus, acancer of the ovary, a cancer of the breast, and an oral squamous cellcancer, encephaloma) or a blood cancer is expected.

1. A compound represented by the following formula (1):

wherein A represents an alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic group, the group A may have a substituent; the ring Brepresents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the monocyclic heterocyclic ring, the ring Bmay have a substituent; the ring C represents an aromatic ring, the ringC may have a substituent; L represents a linker comprising a main chainhaving 3 to 5 atoms selected from the group consisting of a carbon atom,a nitrogen atom, an oxygen atom and a sulfur atom, wherein at least oneatom in the main chain is a hetero atom selected from the groupconsisting of a nitrogen atom, an oxygen atom and a sulfur atom, thelinker L may have a substituent; and n is 0 or 1; with the proviso that(i) when n is 0, the ring B is a condensed ring containing a 5- to8-membered monocyclic heterocyclic ring, (ii) when the ring C is amonocyclic arene ring, the ring C has a substituent, (iii) when thelinker L is a linker represented by the following formula (1-a1):

the group A is a group other than 2-methylaminopyrimidin-4-yl group andthe ring C is a ring other than 9-fluorenyl group, (iv) when the linkerL is a linker represented by the following formula (1-a2):

wherein X¹ represents methyl group and the ring C is a benzene ringhaving a halogen atom as a substituent, the ring B is a ring other than3,4-isoxazole-diyl group; or a salt thereof.
 2. A compound or a saltthereof according to claim 1, wherein in the formula (1) the linker Lcontains a urethane bond.
 3. A compound or a salt thereof according toclaim 1, wherein in the formula (1) the linker L is any one of thefollowing formulae (1-a1) to (1-a6):

wherein X¹ represents an alkyl group.
 4. A compound or a salt thereofaccording to claim 1, wherein in the formula (1) the group A is an arylor heterocyclic group having at least one substituent selected from thegroup consisting of a halogen atom, an alkyl group, a hydroxyl group, analkoxy group, a mercapto group and an alkylthio group.
 5. A compound ora salt thereof according to claim 4, wherein in the formula (1) thegroup A is a phenyl group having substituent(s) on 2-position and/or4-position.
 6. A compound or a salt thereof according to claim 1,wherein in the formula (1) the ring B is an aromatic heterocyclic ringcontaining at least one hetero atom selected from the group consistingof a nitrogen atom, an oxygen atom and a sulfur atom as a constituentatom thereof.
 7. A compound or a salt thereof according to claim 1,wherein in the formula (1) the ring B is an aromatic heterocyclic ringselected from the group consisting of a pyrrole ring, a furan ring, athiophene ring, an imidazole ring, a pyrazole ring, a thiazole ring, anisothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazolering, a pyridine ring, a pyrimidine ring and a quinoline ring.
 8. Acompound or a salt thereof according to claim 1, wherein in the formula(1) the ring B is a thiazole ring, an isothiazole ring or a pyrazolering.
 9. A compound or a salt thereof according to claim 1, wherein inthe formula (1) the ring C is a ring selected from the group consistingof a monocyclic arene ring having a substituent, a condensed arene ringwhich may have a substituent, and a monocyclic or condensed heterocyclicring which may have a substituent.
 10. A compound or a salt thereofaccording to claim 1, wherein in the formula (1) the ring C is any oneof the following formulae (4-a) to (4-c):

wherein Z¹ represents a halogen atom, an alkyl group, a hydroxyl group,an alkoxy group, a mercapto group, an alkylthio group, anN-alkyl-substituted amino group or an N-acyl-substituted amino group; Z²represents an alkyl group or an acyl group; Z³ represents an alkyl groupor acyl group; the ring C¹ represents a C₆₋₁₀arene ring; the ring C²represents a 5- to 8-membered heterocyclic ring comprising G¹ and G²,the ring containing at least one hetero atom selected from the groupconsisting of N, O, and S as a constituent atom thereof; the ring C³represents a 5- to 8-membered heterocyclic ring comprising G⁴ of thering adjacent thereto, the ring C³ containing at least one hetero atomselected from the group consisting of N, O and S as a constituent atomthereof; G¹ to G³ each represent N, O, S, NH, CH or CH₂ depending on thearomaticity or nonaromaticity of the ring C² or that of the 5-memberedring adjacent to the ring C³; G⁴ represents N, C or CH depending on thearomaticity or nonaromaticity of the 5-membered ring adjacent to thering C³; p is an integer of 1 to 5; and q is an integer of 0 to
 6. 11. Acompound represented by any one of the following formulae (6-a) to(6-c):

wherein R¹ and R² are the same or different and each represent a halogenatom, an alkyl group, a hydroxyl group, an alkoxy group, a mercaptogroup or an alkylthio group; the ring B represents a thiazole ring, anisothiazole ring or a pyrazole ring, the ring B may have at least onesubstituent selected from the group consisting of an alkyl group, ahaloalkyl group, a cycloalkyl group, an aryl group, an aralkyl group andan acyl group; L represents a linker selected from the group consistingof formulae (1-a1) to (1-a6) recited in claim 3; Z^(a) represents ahydroxyl group, an alkoxy group, a mercapto group, an alkylthio group,an N-alkyl-substituted amino group or an N-acyl-substituted amino group;Z^(b) represents a hydrogen atom, an alkyl group, a hydroxyl group or analkoxy group; G¹ represents N, CH or CH₂ depending on the aromaticity ornonaromaticity of the ring C²; G² represents N, O or NH; and the ringC², the ring C³, Z², Z³ and q have the same meanings as defined above;or a salt thereof.
 12. A pharmaceutical composition comprising: acompound recited in claim 1 or a pharmaceutically acceptable saltthereof and a carrier.
 13. A p27^(Kip1) ubiquitination inhibitorcomprising, as an effective ingredient, a compound represented by thefollowing formula (1):

wherein A represents an alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic group, the group A may have a substituent; the ring Brepresents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the heterocyclic ring, the ring B may have asubstituent; the ring C represents an aromatic ring, the ring C may havea substituent; L represents a linker comprising a main chain having 3 to5 atoms selected from the group consisting of a carbon atom, a nitrogenatom, an oxygen atom and a sulfur atom, wherein at least one atom in themain chain is a hetero atom selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, the linker L may have asubstituent; and n is 0 or 1; with the proviso that (i) when n is 0, thering B is a condensed ring containing a 5- to 8-membered monocyclicheterocyclic ring, (ii) when the ring C is a monocyclic arene ring, thering C has a substituent; or a pharmaceutically acceptable salt thereof.14. A p27^(Kip1) degradation inhibitor comprising, as an effectiveingredient, a compound or a pharmaceutically acceptable salt thereofrecited in claim
 13. 15. An agent for preventing and/or treating a cellproliferative disease, comprising, as an effective ingredient, acompound represented by the following formula (1):

wherein A represents an alkyl group, a cycloalkyl group, an aryl groupor a heterocyclic group, the group A may have a substituent; the ring Brepresents a 5- to 8-membered monocyclic heterocyclic ring or acondensed ring containing the heterocyclic ring, the ring B may have asubstituent; the ring C represents an aromatic ring, the ring C may havea substituent; L represents a linker comprising a main chain having 3 to5 atoms selected from the group consisting of a carbon atom, a nitrogenatom, an oxygen atom and a sulfur atom, wherein at least one atom in themain chain is a hetero atom selected from the group consisting of anitrogen atom, an oxygen atom and a sulfur atom, the linker L may have asubstituent; and n is 0 or 1; with the proviso that (i) when n is 0, thering B is a condensed ring containing a 5- to 8-membered monocyclicheterocyclic ring, (ii) when the ring C is a monocyclic arene ring, thering C has a substituent, (iii) when the linker L is a linkerrepresented by the following formula (1-a2):

wherein X¹ represents methyl group and the ring C is a benzene ringhaving a halogen atom as a substituent, the ring B is a ring other than3,4-isoxazole-diyl group; or a pharmaceutically acceptable salt thereof.16. An agent according to claim 15, wherein the cell proliferativedisease is at least one member selected from the group consisting ofcancer, rheumatism, diabetes, adiposis, endometriosis, prostatomegaly,and inflammation.